Stat3protein & immunocompetent cells in psoriasis pathogenesis

STAT 3 Protein & Immuno STAT 3 Protein & Immuno Competent Cells in Psoriasis Competent Cells in Psoriasis

PathogenesisPathogenesisM.YOUSRY ABDEL-MAWLA,MDM.YOUSRY ABDEL-MAWLA,MD

Zagazig Faculty of Medicine,Egypt.Zagazig Faculty of Medicine,Egypt.

SignalSignal transducerstransducers andand activatorsactivators ofof transcriptiontranscription) ) Stat) FamilyStat) Family

StatsStats areare latentlatent inin thethe cytoplasmcytoplasm untiluntil theythey areare activatedactivated byby extracellularextracellular signalingsignaling ligandsligands, , includingincluding cytokinescytokines, , growthgrowth factorsfactors andand hormones.hormones.Binding of these extracellular ligands to the Binding of these extracellular ligands to the specific receptors leads to activation of specific receptors leads to activation of various various Tyrosine kinases (TKs). Tyrosine kinases (TKs). They include JAKs, receptor TKs, and non-They include JAKs, receptor TKs, and non-receptor TKs such as Src and ABL, which can receptor TKs such as Src and ABL, which can directly phosphorylate Stat proteins in the directly phosphorylate Stat proteins in the absence of ligand-induced receptor signaling absence of ligand-induced receptor signaling

Cytokines and growth factors that activate STAT proteins

Structure of STAT3 protein.Structure of STAT3 protein.

Similar to other members of the STAT family, Similar to other members of the STAT family, STAT3 is comprised of six domains: N-STAT3 is comprised of six domains: N-terminal domain, coiled-coil domain, DNA terminal domain, coiled-coil domain, DNA binding domain, linker domain, SH2 domain binding domain, linker domain, SH2 domain and Tran activation domain.and Tran activation domain.

STAT3 ActivationSTAT3 Activation

Stat3 is activated by cytokines of the IL-6 Stat3 is activated by cytokines of the IL-6 family such as IL-6, IL-11, leukemia inhibitory family such as IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M and cardiotropin I .(CNTF), oncostatin M and cardiotropin I .Stat3 is the major signal transducer Stat3 is the major signal transducer downstream of gp130-like receptorsdownstream of gp130-like receptors . .Other extracellular signaling ligands such Other extracellular signaling ligands such as IL-10 family members, epidermal growth as IL-10 family members, epidermal growth factor (EGF), platelet derived growth factor factor (EGF), platelet derived growth factor (PDGF), hepa- tocyte growth factor (HGF), (PDGF), hepa- tocyte growth factor (HGF), granulocyte colony- stimulating factor (G-granulocyte colony- stimulating factor (G-CSF) and leptin have also known to CSF) and leptin have also known to activate Stat3. activate Stat3.

Mechanism of Stat3 signalingMechanism of Stat3 signaling

Different tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such as Different tyrosine kinases (TKs) can induce Stat3 activation. Growth factors such as EGF bind to receptor tyrosine kinases (RTKs), followed by phosphorylation of Stat3 EGF bind to receptor tyrosine kinases (RTKs), followed by phosphorylation of Stat3 through activation of intermediary kineases of the SRC and JAK families. Cytokines through activation of intermediary kineases of the SRC and JAK families. Cytokines such as IL-6 family members bind to gp130, a common receptor subunit, thereby JAK such as IL-6 family members bind to gp130, a common receptor subunit, thereby JAK families and subsequent Stat3 are activated. Non-receptor TKs such as SRC families and subsequent Stat3 are activated. Non-receptor TKs such as SRC and ABL can directly phophorylate Stat3 in the absence of ligand-dependent and ABL can directly phophorylate Stat3 in the absence of ligand-dependent receptor signaling. In any pathway, two tyrosine phosphorylated Stat3 proteins form receptor signaling. In any pathway, two tyrosine phosphorylated Stat3 proteins form dimers, enter the nucleus and bind DNA to activate transcription of the target genesdimers, enter the nucleus and bind DNA to activate transcription of the target genes

Regulation of the STAT3 signal Regulation of the STAT3 signal transduction pathwaytransduction pathway

Cytokine-binding induces receptor oligomerization that Cytokine-binding induces receptor oligomerization that facilitates cross-phosphorylation and activation of receptor-facilitates cross-phosphorylation and activation of receptor-associated JAK kinases. associated JAK kinases. Recruitment of STAT3 proteins to the activated receptor Recruitment of STAT3 proteins to the activated receptor complex results in their activation, dimerization and complex results in their activation, dimerization and translocation into the nucleustranslocation into the nucleusIn the nucleus they to induce the expression of cytokine-In the nucleus they to induce the expression of cytokine-responsive genes including, SOCS3 and to a lesser extent, responsive genes including, SOCS3 and to a lesser extent, SOCS1. SOCS proteins inhibit or terminate JAK/STAT signals SOCS1. SOCS proteins inhibit or terminate JAK/STAT signals by binding to tyrosine-phosphorylated JAKs and/or cytokine by binding to tyrosine-phosphorylated JAKs and/or cytokine receptors and targeting them for degradation. receptors and targeting them for degradation. The STAT3signal can also be attenuated by PIAS3, a member of The STAT3signal can also be attenuated by PIAS3, a member of the protein inhibitors of activated STATs (PIAS) family of the protein inhibitors of activated STATs (PIAS) family of proteins. PIAS3 binds selectively to activated STAT3 dimers proteins. PIAS3 binds selectively to activated STAT3 dimers and blocks their ability to activate gene transcription.and blocks their ability to activate gene transcription.

Regulation of the STAT3 signal Regulation of the STAT3 signal transduction pathwaytransduction pathway

Regulation of intracellular Stat3 Regulation of intracellular Stat3 signallingsignalling..

JAK/Stat pathway activation and inhibition.JAK/Stat pathway activation and inhibition.

Upon cytokine binding to its receptor, JAK/Stat pathway is activated (left) Upon cytokine binding to its receptor, JAK/Stat pathway is activated (left) leading to sequential cell response. leading to sequential cell response. The signaling process can be inhibited (right) by The signaling process can be inhibited (right) by (1)(1) JAK degradation through JAK degradation through ubiquitin-proteasome system (Ub), (ubiquitin-proteasome system (Ub), (2)2) dephosphorylate in cytoplasmic PTP1B dephosphorylate in cytoplasmic PTP1B or or (3)(3) nuclear phosphatase (NPTP), or ( nuclear phosphatase (NPTP), or (4)4) by blocking the by blocking the StatStat dimer formation dimer formation Deng et al., Deng et al., Current Cancer Drug TargetsCurrent Cancer Drug Targets, 2007, 7, 2007, 7, , 91-10791-107

Small Molecule Inhibitors of Stat3 Small Molecule Inhibitors of Stat3 Signaling PathwaySignaling Pathway

Compelling evidence from mechanistic studies with antisense, RNA Compelling evidence from mechanistic studies with antisense, RNA interference (RNAi), peptides, and small molecular inhibitors indicate interference (RNAi), peptides, and small molecular inhibitors indicate that blocking Stat3 signaling can lead to successful suppression of that blocking Stat3 signaling can lead to successful suppression of tumor cell growth and apoptosis. tumor cell growth and apoptosis. Thus, Stat3 is an attractive molecular target for the development of Thus, Stat3 is an attractive molecular target for the development of novel therapeutics. novel therapeutics. These small molecular inhibitors, are divided into five classes of These small molecular inhibitors, are divided into five classes of compounds. compounds. They include They include (1) Natural products and derivatives, such as curcumin, (1) Natural products and derivatives, such as curcumin, resveratrol and others. resveratrol and others. (2) Tyrphostins. (2) Tyrphostins. (3) Patinum-containing complexes.(3) Patinum-containing complexes. (5) Azaspiranes. (5) Azaspiranes. Some compounds may have multiple targets including Stat3 protein. Some compounds may have multiple targets including Stat3 protein. Stat3 targeted small molecules will be beneficial for database Stat3 targeted small molecules will be beneficial for database development and template design for future drug developmentdevelopment and template design for future drug development (( Deng, Deng, etal., etal., Current Cancer Drug TargetsCurrent Cancer Drug Targets, 2007, 7, 2007, 7, , 91-10791-107))

Effects of STAT3 Deficiency on Effects of STAT3 Deficiency on Cellular FunctionCellular Function

Stuart et al.TStuart et al.The Journal of Immunology, he Journal of Immunology, 2009, 182: 21–282009, 182: 21–28

PsoriasisPsoriasis

Psoriasis is a chronic inflammatory skin Psoriasis is a chronic inflammatory skin disease characterized by excessive disease characterized by excessive proliferation, abnormal differentiation of proliferation, abnormal differentiation of epidermal keratinocytes, vascular epidermal keratinocytes, vascular proliferation, and leukocyte infiltration in the proliferation, and leukocyte infiltration in the dermis and epidermis . dermis and epidermis .

It has been considered that psoriasis It has been considered that psoriasis results from complex, aberrant relationships results from complex, aberrant relationships between the skin and immune system between the skin and immune system as as well as genetic predisposition and well as genetic predisposition and environmental factorsenvironmental factors

PsoriasisPsoriasis

Combined data on psoriasis susceptibility loci

ND:not determinedND:not determined ( (Pietrzak etal Folia Histochem Cytobiol. 2008:46(1): 12 (11-21)

Psoriasis Clinical PresentationPsoriasis Clinical Presentation

Clinical Manifestations of Clinical Manifestations of PsoriasisPsoriasis

Histopathology of PsoriasisHistopathology of Psoriasis

Histology of healthy (A) and psoriatic (B) skin. Psoriatic skin shows epidermal Histology of healthy (A) and psoriatic (B) skin. Psoriatic skin shows epidermal acantohosis, elongation of rete ridges (indicated by arrows) with reciprocal acantohosis, elongation of rete ridges (indicated by arrows) with reciprocal elongation of intervening dermal papillae and inflammatory infiltrate (40X elongation of intervening dermal papillae and inflammatory infiltrate (40X magnificationmagnification). ).

Immunopathology of PsoriasisImmunopathology of Psoriasis

Psoriasis is initiated and maintained through a multifaceted interplay Psoriasis is initiated and maintained through a multifaceted interplay between keratinocytes, blood vessels, gene expression, and the between keratinocytes, blood vessels, gene expression, and the immune system.immune system.The development of psoriatic plaque begins with antigen recognition The development of psoriatic plaque begins with antigen recognition and uptake by antigen-presenting cells (APC) and uptake by antigen-presenting cells (APC) In psoriasis the dendritic cells (DC) are the most common type of In psoriasis the dendritic cells (DC) are the most common type of antigen-presenting cells. antigen-presenting cells. Antigens are presented on the DC surface usually as MHC class II Antigens are presented on the DC surface usually as MHC class II molecules, which can be recognized by T cell receptor of molecules, which can be recognized by T cell receptor of CD4+ TCD4+ T cells.cells. In addition DCs can present antigens on MHC class I molecules, In addition DCs can present antigens on MHC class I molecules, which lead to the activation of which lead to the activation of CD8+ TCD8+ T cells. DCs also enhance the cells. DCs also enhance the production of adhesion and co-stimulatory molecules to facilitate its production of adhesion and co-stimulatory molecules to facilitate its interaction with T cells (interaction with T cells (Sabat et al. 2007 Exp Dermatol 16:779-Sabat et al. 2007 Exp Dermatol 16:779-798.798.).).


NaiveNaive T (CD4+ )cellsT (CD4+ )cells have to go through maturation in lymphatic have to go through maturation in lymphatic tissues. tissues. CD4+ TCD4+ T cells have a strong affinity to MHC II-peptide complex and they cells have a strong affinity to MHC II-peptide complex and they stick together by forming an immunological synapsis. stick together by forming an immunological synapsis. Interaction between ICAM-1, produced by DCs, and LFA-1, from T Interaction between ICAM-1, produced by DCs, and LFA-1, from T cells, is one of the most important in order to facilitate the DC-T cell cells, is one of the most important in order to facilitate the DC-T cell interaction. interaction. Naive T cellsNaive T cells can mature either to can mature either to Th1, Th2, Th17Th1, Th2, Th17 or regulatory T cells or regulatory T cells and subtype is guided by the selection of a soluble mediator present and subtype is guided by the selection of a soluble mediator present during the activation of naive T cells. After the activation, during the activation of naive T cells. After the activation, T cellsT cells express cutaneous lymphocyte-associated antigen (express cutaneous lymphocyte-associated antigen (CLACLA), which ), which directs directs T cellsT cells to inflamed skin. to inflamed skin. P- and E-selectins expressed by endothelial cells are also important P- and E-selectins expressed by endothelial cells are also important for T cell skin homing (for T cell skin homing (Sabat et al. 2007 Exp Dermatol 16:779-798.Sabat et al. 2007 Exp Dermatol 16:779-798.).).


In inflamed skin, In inflamed skin, T cellsT cells enter the tissue and participate in the enter the tissue and participate in the inflammation reaction. inflammation reaction. Interaction between P- and E- selectins and CLA, as well as other Interaction between P- and E- selectins and CLA, as well as other selectin ligands, facilitate leukocytes rolling along the blood vessel selectin ligands, facilitate leukocytes rolling along the blood vessel wall as they decrease the rolling velocity. wall as they decrease the rolling velocity. Expressions of P- and E-selectins are upregulated in psoriatic skin, Expressions of P- and E-selectins are upregulated in psoriatic skin, possibly stiffening the inflammation observed in psoriatic plaque. possibly stiffening the inflammation observed in psoriatic plaque. T cellsT cells recognize chemokines secreted by the endothelial cells, recognize chemokines secreted by the endothelial cells, become active and a tight adhesion, facilitated by integrins become active and a tight adhesion, facilitated by integrins produced by produced by T cellsT cells and their ligands expressed by endothelial cells, and their ligands expressed by endothelial cells, is formed between the cells. is formed between the cells. The most important molecule in skin homing is LFA-1 binding to The most important molecule in skin homing is LFA-1 binding to ICAM-2. T cells probably enter the endothelial wall through pores ICAM-2. T cells probably enter the endothelial wall through pores formed between endothelial cells in an integrin-dependent process formed between endothelial cells in an integrin-dependent process called diapedesiscalled diapedesis ((Sabat et al. 2007 Exp Dermatol 16:779-798.Sabat et al. 2007 Exp Dermatol 16:779-798.).).


In the skin In the skin T cellsT cells are reactivated by different kinds of APCs, which are reactivated by different kinds of APCs, which also include keratinocytes. Interferon- (IFN-), produced by APCs, also include keratinocytes. Interferon- (IFN-), produced by APCs, has an important role in has an important role in T cellT cell reactivation and proliferation. reactivation and proliferation. T cellsT cells in psoriatic skin have prolonged and increased IFN- in psoriatic skin have prolonged and increased IFN- response when compared to healthy skin. Interferon- enhances INF-response when compared to healthy skin. Interferon- enhances INF-expression in expression in T cellsT cells. . Also cytokines produced by APCs, especially Also cytokines produced by APCs, especially IL-23IL-23 and and IL-6IL-6, have , have an important role in reactivation. an important role in reactivation. After reactivation After reactivation T cellsT cells express a variety of cytokines. express a variety of cytokines. T cell response leads to the activation of keratinocytes and the T cell response leads to the activation of keratinocytes and the activation is carried out by activation is carried out by Th17Th17 and different cytokines produced by and different cytokines produced by macrophages, DCs and keratinocytes themselves. macrophages, DCs and keratinocytes themselves. Keratinocyte activation leads to their increased proliferation and Keratinocyte activation leads to their increased proliferation and alterations in the maturation process.alterations in the maturation process. Activated keratinocytes produce a vast variety of mediators, which Activated keratinocytes produce a vast variety of mediators, which further promote immigration of inflammatory cells and induce further promote immigration of inflammatory cells and induce angiogenesis, thus enhancing phenomena relevant for the angiogenesis, thus enhancing phenomena relevant for the pathogenesis of psoriasis (pathogenesis of psoriasis (Sabat et al. 2007 Exp Dermatol Sabat et al. 2007 Exp Dermatol 16:779-798 &. 16:779-798 &. Boehncke et al Boehncke et al JEADV 2010, 24 Suppl. 5, 2–24JEADV 2010, 24 Suppl. 5, 2–24)). .

One previous psoriasis model demonstrated that overexpression of One previous psoriasis model demonstrated that overexpression of the angiopoietin receptor the angiopoietin receptor Tie2Tie2 in endothelial cells and keratinocytes in endothelial cells and keratinocytes led to the development of a psoriasiform phenotype. led to the development of a psoriasiform phenotype. Two new mouse models have been engineered whereby Two new mouse models have been engineered whereby Tie2Tie2 expression is confined to either endothelial cells or keratinocytes. expression is confined to either endothelial cells or keratinocytes. Both lines of mice have significant increases in dermal vasculature Both lines of mice have significant increases in dermal vasculature but only the KC-but only the KC-Tie2-Tie2-overexpressing mice developed a cutaneous overexpressing mice developed a cutaneous psoriasiform phenotype. psoriasiform phenotype. These mice spontaneously developed characteristic hallmarks of These mice spontaneously developed characteristic hallmarks of human psoriasis, including extensive acanthosis, increases in dermal human psoriasis, including extensive acanthosis, increases in dermal CD4+ T cells, infiltrating epidermal CD8+ T cells, dermal dendritic cells CD4+ T cells, infiltrating epidermal CD8+ T cells, dermal dendritic cells and macrophages, and increased expression of cytokines and and macrophages, and increased expression of cytokines and chemokines associated with psoriasis, including interferon- , tumor chemokines associated with psoriasis, including interferon- , tumor necrosis factor- , and interleukins 1 , 6, 12, 22, 23, and 17. Host-necrosis factor- , and interleukins 1 , 6, 12, 22, 23, and 17. Host-defense molecules, cathelicidin, β-defensin, and S100A8/A9, were also defense molecules, cathelicidin, β-defensin, and S100A8/A9, were also up-regulated in the hyperproliferative skin. up-regulated in the hyperproliferative skin. Therefore, confining Therefore, confining Tie2Tie2 overexpression solely to keratinocytes overexpression solely to keratinocytes results in a mouse model that meets the clinical, histological, results in a mouse model that meets the clinical, histological, immunophenotypic, biochemical, and pharmacological criteria immunophenotypic, biochemical, and pharmacological criteria required for an animal model of human psoriasis (required for an animal model of human psoriasis (Wolfram et al,Wolfram et al,American American Journal of Pathology.Journal of Pathology. 2009 174:1443-1458 ) 2009 174:1443-1458 ). .

Following a trigger or stimulus, dendritic cells and T cells are activated, leading to the formation Following a trigger or stimulus, dendritic cells and T cells are activated, leading to the formation of an ‘immunological synapse’ that enhances their of an ‘immunological synapse’ that enhances their interactions. interactions. This ‘immunologic synapse’ results in the release of cytokines, chemokines and growth This ‘immunologic synapse’ results in the release of cytokines, chemokines and growth factors that trigger keratinocyte proliferation, altered differentiation and angiogenesis.factors that trigger keratinocyte proliferation, altered differentiation and angiogenesis. Within the chronic psoriatic plaque, a vicious cycle of continuous T cell and dendritic cell Within the chronic psoriatic plaque, a vicious cycle of continuous T cell and dendritic cell activation is envisionedactivation is envisioned ((Nickoloff & Nestle : Nickoloff & Nestle : J Clin Invest 2004; 113: 1664–1675.).J Clin Invest 2004; 113: 1664–1675.).

Immunopathology of PsoriasisImmunopathology of Psoriasis((((Nickoloff & Nickoloff &

Nestle : J Clin Invest 2004; 113: 1664–1675.).Nestle : J Clin Invest 2004; 113: 1664–1675.).

Bidirectional flow of ‘information’ and cells in a Bidirectional flow of ‘information’ and cells in a mature psoriasis lesionmature psoriasis lesion

There is close interdependence of the There is close interdependence of the epidermis and dermal inflammatory infiltrate, epidermis and dermal inflammatory infiltrate, as well as a balance between the innate and as well as a balance between the innate and acquired immune systems. acquired immune systems. Chemokines produced by keratinocytes in Chemokines produced by keratinocytes in the epidermis act on both the innate and the epidermis act on both the innate and acquired immune systems, stimulating DCs, acquired immune systems, stimulating DCs, neutrophils and other innate mediators as neutrophils and other innate mediators as well as T cells. well as T cells. Keratinocytes also release cytokines and Keratinocytes also release cytokines and growth factors, leading to altered gene growth factors, leading to altered gene expression and regenerative hyperplasia.expression and regenerative hyperplasia.

Bidirectional flow of ‘information’ and cells in a Bidirectional flow of ‘information’ and cells in a mature psoriasis lesionmature psoriasis lesion

Immune-system-derived cytokines, in turn, Immune-system-derived cytokines, in turn, act on keratinocytes to either induce act on keratinocytes to either induce inflammatory genes or increase proliferation.inflammatory genes or increase proliferation. Meanwhile, in the lymphoid-like tissue of the Meanwhile, in the lymphoid-like tissue of the psoriatic dermis, molecules of the innate and psoriatic dermis, molecules of the innate and acquired immune systems also interact. acquired immune systems also interact. The genetic underpinnings of psoriasis are The genetic underpinnings of psoriasis are known to be complex, with ten or more known to be complex, with ten or more susceptibility loci, and these probably susceptibility loci, and these probably interact with various environmental factors interact with various environmental factors that act on the skin and/or immune systemthat act on the skin and/or immune system..

Keratinocytes cross talks among Keratinocytes cross talks among immune cellsimmune cells in psoriasisin psoriasis

Psoriasis: Evidence of Psoriasis: Evidence of T-Cell MediationT-Cell Mediation

Early cells in psoriatic lesionsEarly cells in psoriatic lesionsCyclosporine, anti-CD4 monoclonal Cyclosporine, anti-CD4 monoclonal antibodies are used as treatmentantibodies are used as treatmentBlocking T cell:APC 2nd signal Blocking T cell:APC 2nd signal prevents psoriatic lesionprevents psoriatic lesionPsoriasis altered in HIV infectionPsoriasis altered in HIV infectionStreptococcal superantigens can Streptococcal superantigens can induce psoriasisinduce psoriasis

T-Cell in PsoriasisT-Cell in Psoriasis

The pathogenesis of psoriasis is a multistep The pathogenesis of psoriasis is a multistep process, and an array of process, and an array of cytokinescytokines has an has an impressive role in these processes . impressive role in these processes . IL-2IL-2 and and IFN-γIFN-γ are two important cytokines, are two important cytokines, which secreted upon which secreted upon Th1Th1 activation. activation. These cytokines activate different signal These cytokines activate different signal transducers and augment transcription of a transducers and augment transcription of a large group of immune related genes and large group of immune related genes and may contribute to the overall pathogenic may contribute to the overall pathogenic process (process (Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91))

T-Cell in PsoriasisT-Cell in PsoriasisThe The Th1Th1 character of psoriasis is supported by the character of psoriasis is supported by the development of skin lesions in quiescent patients treated development of skin lesions in quiescent patients treated with with IL-2IL-2 for cancer therapy. for cancer therapy. Conversely, a therapeutic effect, accompanied by a shift Conversely, a therapeutic effect, accompanied by a shift toward Th2 cytokine expression patterns, is seen in toward Th2 cytokine expression patterns, is seen in psoriasis patients following administration of the psoriasis patients following administration of the Th2Th2 cytokine, cytokine, IL-10IL-10. . T cellsT cells cloned from psoriatic skin can variously produce cloned from psoriatic skin can variously produce IFNIFN-, -, TGFTGF-, -, IL-2IL-2, , IL-3IL-3, , IL-6IL-6, , IL-8IL-8, and , and GM-CSFGM-CSF, although , although none of these are singly responsible for none of these are singly responsible for T cellT cell stimulation stimulation of keratinocyte growth, which appears to involve of keratinocyte growth, which appears to involve IFNIFN- in - in concert with other cytokines .concert with other cytokines . IL-7IL-7 , , produced by both T cells & keratinocytes, is also produced by both T cells & keratinocytes, is also present at elevated levels in lesional psoriatic compared present at elevated levels in lesional psoriatic compared with nonlesional and normal skinwith nonlesional and normal skin ( ( Mollison et alMollison et al Journal of Investigative DermatologyJournal of Investigative Dermatology ,1999, 112: 729– ,1999, 112: 729–738;) .738;) .

Serum cytokine levels of psoriatic patients and Serum cytokine levels of psoriatic patients and

controlscontrols ((Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91Z Jadali et alIranian J Publ Health, Vol. 36, No.2, 2007, pp.87-91))

Serum levels of s IL - 2R in patients with psoriasis vulgaris Serum levels of s IL - 2R in patients with psoriasis vulgaris compared to healthy controlscompared to healthy controls ((Halla M. Ragab et al Halla M. Ragab et al J. of J. of American Science 2010;6(10):423-429American Science 2010;6(10):423-429))

Serum levels of IL - 6 in patients with psoriasis Serum levels of IL - 6 in patients with psoriasis vulgaris compared to healthy controlsvulgaris compared to healthy controls ((Halla M. Halla M. Ragab et al Ragab et al J. of American Science 2010;6(10):423-J. of American Science 2010;6(10):423-429429))

Serum IL17 & IL22 in psoriasis Serum IL17 & IL22 in psoriasis Inas Almakhzangy & A. Gaballa Egyptian Dermatology Online Journal 5 (1): 4, 2009

T Helper 1 versus 2 in T Helper 1 versus 2 in psoriasispsoriasis

Psoriasis is an inflammatory skin disorder characterized by increased Psoriasis is an inflammatory skin disorder characterized by increased activation of CD4+ T lymphocytes, and systemic and local activation of CD4+ T lymphocytes, and systemic and local overexpression of pro-inflammatory cytokines such as interleukin 2 (IL-overexpression of pro-inflammatory cytokines such as interleukin 2 (IL-2), gamma interferon (IFN-), IL-6 and tumour necrosis factor alpha, 2), gamma interferon (IFN-), IL-6 and tumour necrosis factor alpha, indicating that immunopathogenesis of the disease is T helper 1 (Th1) indicating that immunopathogenesis of the disease is T helper 1 (Th1) mediated. mediated. T helper cell precursors (Thp) can be skewed towards mutually T helper cell precursors (Thp) can be skewed towards mutually exclusive Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on exclusive Th1, Th2, Th17 and T regulatory cell (Treg) phenotypes on the basis of the cytokine environmentthe basis of the cytokine environment.. Several studies suggest a pivotal role of bacterial superantigens in the Several studies suggest a pivotal role of bacterial superantigens in the initiation and/or exacerbation of this illness. In contrast to controls, initiation and/or exacerbation of this illness. In contrast to controls, psoriasis patients in the early course of disease were characterized by psoriasis patients in the early course of disease were characterized by significantly increased expression of the pro-inflammatory cytokine significantly increased expression of the pro-inflammatory cytokine IFN-, whilst a shift towards IL-10 secretion (Th2 response) was IFN-, whilst a shift towards IL-10 secretion (Th2 response) was observed in those presenting with increased duration of disease. observed in those presenting with increased duration of disease. These observations suggest a possible shift from a Th1 to a Th2 These observations suggest a possible shift from a Th1 to a Th2 cytokine response with superantigen-associated progression for the cytokine response with superantigen-associated progression for the duration of psoriasis, perhaps as an adaptive process by the immune duration of psoriasis, perhaps as an adaptive process by the immune system in an attempt to downregulate abnormal inflammatory Th1 system in an attempt to downregulate abnormal inflammatory Th1 immune responsesimmune responses ( (Jain etal 2009 Jain etal 2009 J Med Microbiol J Med Microbiol 5858 :180-184). :180-184).

PSORIASIS IS aPSORIASIS IS aTH17 TH17 DISEASE :A HypothesisDISEASE :A Hypothesis

An initiating event such as trauma or skin surface microbes An initiating event such as trauma or skin surface microbes triggers triggers IL-23IL-23 production by keratinocytes and resident production by keratinocytes and resident dendritic cells, which in turn stimulates proliferation of CCR4+ dendritic cells, which in turn stimulates proliferation of CCR4+ and CCR6+and CCR6+Th17Th17 cells found within skin. cells found within skin. These activated These activated Th17Th17 cells secrete Th17 cytokines including cells secrete Th17 cytokines including IL-IL-2222 and and IL-17AIL-17A, which cause keratinocyte growth and activation, , which cause keratinocyte growth and activation, respectively. respectively. Th17 Th17 cytokines also induce CCL20 production by cytokines also induce CCL20 production by keratinocytes, which fosters additional chemotaxis of CCR6+keratinocytes, which fosters additional chemotaxis of CCR6+++Th17Th17 cells and CCR6 dendritic cells from blood into skin. cells and CCR6 dendritic cells from blood into skin. Cytokines released by these newly recruited cells maintain Cytokines released by these newly recruited cells maintain psoriatic psoriatic inflammation (inflammation (Fitch, etal., Current Rheumatology Fitch, etal., Current Rheumatology Reports 2007, 9:461–467Reports 2007, 9:461–467))


CD4+ and CD8+ T-cell clones derived from CD4+ and CD8+ T-cell clones derived from lesional psoriatic skin in humans expressed lesional psoriatic skin in humans expressed IL-17IL-17, irrespective of their IFN-γ or IL-4 , irrespective of their IFN-γ or IL-4 production. production. IL-17 IL-17 expression is detectable in biopsies expression is detectable in biopsies from lesional psoriatic skin, but not in from lesional psoriatic skin, but not in nonlesional control biopsies nonlesional control biopsies Th17Th17 cells are present in the inflammatory cells are present in the inflammatory infiltrate in psoriatic plaques to induce infiltrate in psoriatic plaques to induce enhancement of neutrophil chemotaxis enhancement of neutrophil chemotaxis


The expression of IL-23 is highly enhanced in The expression of IL-23 is highly enhanced in lesional psoriatic skin . lesional psoriatic skin .

This IL 23, a This IL 23, a Th17Th17-inducing factor, is -inducing factor, is produced by keratinocytes, Langerhans cells produced by keratinocytes, Langerhans cells and macrophages. and macrophages.

The enhanced expression of both IL-23 and The enhanced expression of both IL-23 and IL-17 within psoriatic lesions indicates that IL-17 within psoriatic lesions indicates that the IL-23/IL-17 cytokine axis is fully the IL-23/IL-17 cytokine axis is fully operational in the inflamed skin.operational in the inflamed skin.


IL-22, which mediates acanthosis, is IL-22, which mediates acanthosis, is preferentially expressed by preferentially expressed by Th17Th17 cells and, cells and, like like IL-17IL-17, can be induced by IL-23., can be induced by IL-23.

The production of The production of IL-17IL-17 and IL-22, however, and IL-22, however, appears to be differentially regulated. appears to be differentially regulated.

Whereas IL-6 alone can induce IL-22, but not Whereas IL-6 alone can induce IL-22, but not IL-17IL-17, the additional presence of TGFß dose , the additional presence of TGFß dose dependently inhibits the expression of IL-dependently inhibits the expression of IL-22, while it promotes IL-17 production 22, while it promotes IL-17 production

STAT3 REGULATION of CYTOKINE-STAT3 REGULATION of CYTOKINE-MEDIATED GENERATION of TH 17MEDIATED GENERATION of TH 17

IL-6 functions to up-regulate IL-23R and that IL-23 synergized IL-6 functions to up-regulate IL-23R and that IL-23 synergized with IL-6 in promoting THi (with IL-6 in promoting THi (TH17TH17)generation. )generation. STAT3, activated by both IL-6 and IL-23, plays a critical role in STAT3, activated by both IL-6 and IL-23, plays a critical role in THi development. THi development. A hyperactive form of STAT3 promoted THi development, A hyperactive form of STAT3 promoted THi development, whereas this differentiation process was greatly impaired in whereas this differentiation process was greatly impaired in STAT3-deficient T cells. STAT3-deficient T cells. Moreover, STAT3 regulated the expression of retinoic acid Moreover, STAT3 regulated the expression of retinoic acid receptor-related orphan receptor IL-17 -T (RORt), a THi-specific receptor-related orphan receptor IL-17 -T (RORt), a THi-specific transcriptional regulator. transcriptional regulator. STAT3 deficiency impaired ROR t expression and led to elevated STAT3 deficiency impaired ROR t expression and led to elevated expression of T-box expressed in T cells (T-bet) and Forkhead expression of T-box expressed in T cells (T-bet) and Forkhead box P3 (Foxp3). box P3 (Foxp3). There is a pathway whereby cytokines regulate THi There is a pathway whereby cytokines regulate THi differentiation through a selective STAT transcription factor that differentiation through a selective STAT transcription factor that functions to regulate lineage-specific gene expression (functions to regulate lineage-specific gene expression (Yang et Yang et

al.,2007 J.Biol Chem.,282,13:9358al.,2007 J.Biol Chem.,282,13:9358& Egwuagu :Cytokine 47 (2009) 149–156& Egwuagu :Cytokine 47 (2009) 149–156))..

Keratinocytes cross talks with Keratinocytes cross talks with immune cellsimmune cells in psoriasisin psoriasis

T Helper T Helper 17 17 Activation Activation Mechanisms in PsoriasisMechanisms in Psoriasis

(Fitch, etal., Current Rheumatology Reports 2007, 9:461–(Fitch, etal., Current Rheumatology Reports 2007, 9:461–467467))

TH17 cells: effector cytokines and their function.

Th17 cells characterized by production of IL-17A, IL-17F, IL-22, and IL-21.Both IL-22 and IL-21 are not the exclusive cytokines produced byTh17 cells. IL-17A and IL-17F mediate tissue damages during organ specific autoimmunity via variety of mechanism including the activation of matrix metalloproteinases and recruitment o f neutrophils.IL-22 induces skin inflammation. IL-21 mediates amplification of T helper 17 pathway.

Proinflammatory Effects of Proinflammatory Effects of IL17IL17

Adapted from Iwakura & Ishigame, J Clin Invest 116:1218-1222 (2006)

Roles of IL-23 on T Helper 17 cellsRoles of IL-23 on T Helper 17 cellsin Chronic Inflammation in Psoriasisin Chronic Inflammation in Psoriasis

Dendritic cell

Macrophage

IL-23

IL-12

Th1

Th17

IFN

IL-1, IL-6TNF

Inflammatory response

Endothelial cellsStromal cells

Epithelial cellsFibroblasts

Macrophage

IL-17, IL-6 IL-1IL-6IL-8TNF

IL-12R

IL-23R

IL-23R

Roles of IL-23 on T Helper 17 cellsRoles of IL-23 on T Helper 17 cellsin Chronic Inflammation in Psoriasisin Chronic Inflammation in Psoriasis

There is an important role for IL-23-induced There is an important role for IL-23-induced Th17Th17 cells and the cells and the Th17Th17-derived cytokines -derived cytokines IL-17IL-17 and IL-22 and IL-22 in the immunopathogenetic mechanisms underlying in the immunopathogenetic mechanisms underlying psoriasis. psoriasis. A clinical improvement in most psoriasis patients A clinical improvement in most psoriasis patients was observed after therapy with blocking was observed after therapy with blocking monoclonal antibodies against p40, the shared monoclonal antibodies against p40, the shared subunit of the heterodimeric cytokines IL-12 and IL-subunit of the heterodimeric cytokines IL-12 and IL-23. 23. The finding that this treatment causes a The finding that this treatment causes a downregulation of p40 and IL-23 p19, but not of IL-12 downregulation of p40 and IL-23 p19, but not of IL-12 p35 in psoriatic skin lesions suggests that p35 in psoriatic skin lesions suggests that interference with IL-23 rather than IL-12 activity is interference with IL-23 rather than IL-12 activity is responsible for this clinical improvementresponsible for this clinical improvement..

Interleukin-23 (IL-23Interleukin-23 (IL-23) helps to maintain the lesion by leading to the ) helps to maintain the lesion by leading to the development of development of Th17Th17 cells. cells. These in turn produce necrosis factor-alpha (TNF-a), IThese in turn produce necrosis factor-alpha (TNF-a), IL-17L-17 and and IL-22. IL-22. IL-22 IL-22 is believed to drive many of the epidermal changes in is believed to drive many of the epidermal changes in psoriasispsoriasis. . Many autoimmune diseases, including Many autoimmune diseases, including psoriasispsoriasis, are characterized by high , are characterized by high levels of levels of Th17Th17..

Journal of Investigative Dermatology 2009;129:1339–1350Journal of Investigative Dermatology 2009;129:1339–1350..

Toll like Receptor (TLR) in Toll like Receptor (TLR) in Th17Th17-mediated -mediated Autoimmune Inflammation (Autoimmune Inflammation (Goriely S, Neurath M,

Goldman M, Nature Rev Immunol 2007)

IL-23

IL-12

IL-27TLR3

TLR2 Th1

Th1

Th17

IFN-

AutoimmuneInflammation

polyI : C

PGN

IFN-

Cua et al., Nature 421:744, 2003Weaver et al., Immunity 24:677, 2006Mensah-Brown et al., Eur J Immunol 36:216, 2006S Hue et al. J Exp Med 11:2473, 2006

The IL23 – IL17 axis: a critical role in The IL23 – IL17 axis: a critical role in autoimmune inflammationautoimmune inflammation

IL-23 & IL-17 promote inflammatory IL-23 & IL-17 promote inflammatory bowel disease and autoimmune bowel disease and autoimmune experimental encephalomyelitisexperimental encephalomyelitis

IL-17 is overexpressed in multiple IL-17 is overexpressed in multiple sclerosis, rheumatoid arthritis and sclerosis, rheumatoid arthritis and psoriasispsoriasis

Genetic PolymorphismGenetic Polymorphism

Certain genetic changes in IL-12/23p40 and Certain genetic changes in IL-12/23p40 and IL-23R will lead to enhanced IL-23 production IL-23R will lead to enhanced IL-23 production and IL-23 receptor-mediated signaling and and IL-23 receptor-mediated signaling and thus be correlative with psoriasis thus be correlative with psoriasis susceptibility in humans.susceptibility in humans.Certain IL-12/23p40 and IL-23R Certain IL-12/23p40 and IL-23R polymorphisms correlate with certain polymorphisms correlate with certain disease presentations (e.g., guttate vs. disease presentations (e.g., guttate vs. pustular psoriasis) or with severity of pustular psoriasis) or with severity of diseasedisease ..

((Blauvelt Blauvelt J Invest Dermatol. 2008 ; 128(5): J Invest Dermatol. 2008 ; 128(5): 1064–10671064–1067).).

Schematic of the related heterodimers IL-23 and IL-12 and their related Schematic of the related heterodimers IL-23 and IL-12 and their related heterodimeric cytokine receptors, indicating (heterodimeric cytokine receptors, indicating (in red circlesin red circles) the ) the subunits where polymorphisms in genes encoding these proteins subunits where polymorphisms in genes encoding these proteins have been linked to development of psoriasishave been linked to development of psoriasis ( (Blauvelt Blauvelt J Invest J Invest Dermatol. 2008 128(5): 1064–1067Dermatol. 2008 128(5): 1064–1067).).

Stat3 links activated keratinocytes and Stat3 links activated keratinocytes and immunocytes required for development immunocytes required for development

of psoriasisof psoriasis Epidermal keratinocytes in psoriatic lesions are characterized Epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3. by activated Stat3. Transgenic mice with keratinocytes expressing a constitutively Transgenic mice with keratinocytes expressing a constitutively active Stat3 (active Stat3 (K5.Stat3C miceK5.Stat3C mice) develop a skin phenotype either ) develop a skin phenotype either spontaneously, or in response to wounding, that closely spontaneously, or in response to wounding, that closely resembles psoriasis.resembles psoriasis.Keratinocytes from Keratinocytes from K5.Stat3C miceK5.Stat3C mice show upregulation of show upregulation of several molecules linked to the pathogenesis of psoriasis.several molecules linked to the pathogenesis of psoriasis. In addition, the development of psoriatic lesions in In addition, the development of psoriatic lesions in K5.Stat3CK5.Stat3C mice requires cooperation between Stat3 activation in mice requires cooperation between Stat3 activation in keratinocytes and activated T cells. keratinocytes and activated T cells. Finally, abrogation of Stat3 function by a decoy oligonucleotide Finally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions in inhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice. K5.Stat3C mice. Thus, targeting Stat3Thus, targeting Stat3 may be potentially therapeutic in the may be potentially therapeutic in the treatment of psoriasis.treatment of psoriasis.

A positive feedback mechanism for A positive feedback mechanism for Th1/Th17 inflammationTh1/Th17 inflammation..

Th1 cells, but,not Th2 cells, produce an endogenous ligand Th1 cells, but,not Th2 cells, produce an endogenous ligand for Toll-like receptor (TLR) 4, namely extradomain A+ for Toll-like receptor (TLR) 4, namely extradomain A+ fibronectin containing extra type III domain A (FnEDA+).fibronectin containing extra type III domain A (FnEDA+).

As TLR4 stimulation leads to production of As TLR4 stimulation leads to production of proinflammatory cytokines that recruit (via altered proinflammatory cytokines that recruit (via altered endothelial adhesion molecule expression and chemokine endothelial adhesion molecule expression and chemokine production) more Th1/Th17 cells, a positive feedback production) more Th1/Th17 cells, a positive feedback mechanism for Th1/Th17 inflammation exists .mechanism for Th1/Th17 inflammation exists .

FnEDA+ positive feedback loops are a potential driver of FnEDA+ positive feedback loops are a potential driver of Th1/Th17 Th1/Th17 ininflammation flammation (John (John P. McFadden et al Clinics in P. McFadden et al Clinics in Dermatology (2011) 29, 257–265).Dermatology (2011) 29, 257–265).

Skin trauma is one of the best-known stimuli for psoriasis Skin trauma is one of the best-known stimuli for psoriasis plaque formation (the Koebner phenomenon). plaque formation (the Koebner phenomenon).

After wound injury, TGF-β upregulates FnEDA+ and α5β1 After wound injury, TGF-β upregulates FnEDA+ and α5β1 integrin expres-macrophages) stimulation by FnEDA+ can lead integrin expres-macrophages) stimulation by FnEDA+ can lead to production of IL-1β, TNF-α, IL-6, IL-12, and IL-23.to production of IL-1β, TNF-α, IL-6, IL-12, and IL-23.

These cytokines will in turn lead to endothelial expression of These cytokines will in turn lead to endothelial expression of intercellular adhesion molecule-1, E-selectin, and vascular intercellular adhesion molecule-1, E-selectin, and vascular cellular adhesion molecule-1, with augmentation of T-cell cellular adhesion molecule-1, with augmentation of T-cell recruitment into the lesional skin.recruitment into the lesional skin.

Such cytokine production should lead to promotion of Th1 Such cytokine production should lead to promotion of Th1 and Th17 cell activation; and psoriasis is indeed characterized and Th17 cell activation; and psoriasis is indeed characterized by such a cytokine and T-cell profile.by such a cytokine and T-cell profile.

FnEDA+ will cause keratinocytes from psoriatic FnEDA+ will cause keratinocytes from psoriatic individuals (but not nonpsoriatic) to proliferate.individuals (but not nonpsoriatic) to proliferate.

Hyperprolifer-ating keratinocytes produce Hyperprolifer-ating keratinocytes produce proliferative keratins such as keratins 6, 16, and proliferative keratins such as keratins 6, 16, and 17.17.

The observation of close homology between The observation of close homology between proliferative keratin and streptococcal M proliferative keratin and streptococcal M protein31 lead to the proposal that T cells that protein31 lead to the proposal that T cells that recognize epitopes in both proteins are involved recognize epitopes in both proteins are involved in an autoimmune reaction in psoriasis.in an autoimmune reaction in psoriasis.

Such an autoimmune reaction will lead to Such an autoimmune reaction will lead to proinflammatory cytokine release, which in proinflammatory cytokine release, which in turn will lead to recruitment of Th1 and turn will lead to recruitment of Th1 and Th17 cells. Th1 cells will produce Th17 cells. Th1 cells will produce FnEDA+, completing the positive feedback FnEDA+, completing the positive feedback loop.loop.

It remains to be established whether T It remains to be established whether T cells within psoriasis lesions react to cells within psoriasis lesions react to keratin, so the akeratin, so the autoimmune loop remains as a utoimmune loop remains as a hypothetic possibility, hypothetic possibility,

Multiple genes/candidate genes variants Multiple genes/candidate genes variants have been associated with psoriasis.have been associated with psoriasis.

Many of these genes can be accommodated Many of these genes can be accommodated onto a model of psoriasis based on multiple onto a model of psoriasis based on multiple FnEDA+ loops .FnEDA+ loops .

Multiple FnEDA+ loops are operative in Multiple FnEDA+ loops are operative in psoriasis and override regulatory attempts to psoriasis and override regulatory attempts to switch off cutaneous inflammation, which switch off cutaneous inflammation, which may explain why psoriatic inflammatory may explain why psoriatic inflammatory plaques have the potential to persist plaques have the potential to persist indefinitely.indefinitely.

Experimental Models of Experimental Models of PsoriasisPsoriasis

An interesting transgenic mouse model for psoriasis is transgenic An interesting transgenic mouse model for psoriasis is transgenic mouse with constitutively active Stat3 overexpression.mouse with constitutively active Stat3 overexpression. Stat3, participates in cell proliferation, apoptosis, cell differentiation Stat3, participates in cell proliferation, apoptosis, cell differentiation and other important biological functions and other important biological functions In addition, its expression is elevated in psoriasis and in lesional In addition, its expression is elevated in psoriasis and in lesional keratinocytes, particularly in the nuclei of keratinocytes .keratinocytes, particularly in the nuclei of keratinocytes . Stat3 is activated by many different cytokines, including members Stat3 is activated by many different cytokines, including members of IL-20 subfamily cytokines, namely IL-19, IL-20, IL-22 and IL-24, of IL-20 subfamily cytokines, namely IL-19, IL-20, IL-22 and IL-24, which are all upregulated in psoriatic skin .which are all upregulated in psoriatic skin . Of these, IL-22 is produced by Th17 lymphocytes, in contrast to Of these, IL-22 is produced by Th17 lymphocytes, in contrast to the other related cytokines, and its production is induced by IL-23. the other related cytokines, and its production is induced by IL-23. Overexpression of IL-23 is profound in lesional psoriatic skin and Overexpression of IL-23 is profound in lesional psoriatic skin and Stat3 activation via IL-22 seems to be important in the IL-23-induced Stat3 activation via IL-22 seems to be important in the IL-23-induced epidermal acanthosis relevant in the pathogenesis of psoriasis epidermal acanthosis relevant in the pathogenesis of psoriasis ((Zhang et al 2007 J Invest Dermatol, 27:2544-2551 and Zhang et al 2007 J Invest Dermatol, 27:2544-2551 and DANILENKO,2008 Vet Pathol 45:563–575)


The scientists transplanted skin from their STAT3 mice The scientists transplanted skin from their STAT3 mice to a mouse that produces no T cells, a key component of to a mouse that produces no T cells, a key component of the immune system that is believed to be necessary for the immune system that is believed to be necessary for development of psoriasis. development of psoriasis. The transplanted skin did not initially develop psoriasis The transplanted skin did not initially develop psoriasis lesions. lesions. However, when the scientists injected activated T cells However, when the scientists injected activated T cells into the skin grafts on T cell-free mice, the mice then into the skin grafts on T cell-free mice, the mice then developed psoriasis following mild injury. developed psoriasis following mild injury. "This experiment showed it is necessary to have both "This experiment showed it is necessary to have both activated STAT3 in keratinocytes and infiltrating, activated STAT3 in keratinocytes and infiltrating, activated T cells to develop psoriasis. "activated T cells to develop psoriasis. "Neither is Neither is sufficient alone."sufficient alone." ( (DiGiovanni’s et alDiGiovanni’s et al, the Journal Nature , the Journal Nature Medicine ,Jan.2005Medicine ,Jan.2005))


Constitutive activation of Stat3 Constitutive activation of Stat3 mice mice ((K5.Stat3C miceK5.Stat3C mice) ) increased the increased the sensitivity of the epidermis to sensitivity of the epidermis to external stimuli, leading to a external stimuli, leading to a psoriatic phenotype, similar to psoriatic phenotype, similar to the clinical Koebner the clinical Koebner phenomenon(phenomenon(SanoSano etal., Journal of etal., Journal of

Dermatological Science (2008) 50, 1—14Dermatological Science (2008) 50, 1—14))..

Up-regulated molecules in keratinocytes of Up-regulated molecules in keratinocytes of K5.Stat3CK5.Stat3C mice mice

(Sano(Sano etal., Journal of Dermatological Science (2008) 50, 1—etal., Journal of Dermatological Science (2008) 50, 1—1414))

Blocking the function ofBlocking the function of STAT3STAT3 using antisense oligo-using antisense oligo-nucleotides inhibited the onset of, and reversed, nucleotides inhibited the onset of, and reversed, established psoriatic lesionsestablished psoriatic lesions. .

Further analysis revealed a dual requirement of both Further analysis revealed a dual requirement of both activated STAT3 in keratinocytes as well as in T cells, activated STAT3 in keratinocytes as well as in T cells, indicating that the pathogenesis of psoriasis is rooted in a indicating that the pathogenesis of psoriasis is rooted in a co-operative process involving STAT3-regulated genes in co-operative process involving STAT3-regulated genes in both skin cells and the immune system .both skin cells and the immune system .

Phosphatyrosyl peptides block STAT3-mediated DNA Phosphatyrosyl peptides block STAT3-mediated DNA binding activity, gene regulation and cell transformation. binding activity, gene regulation and cell transformation.

((VaradwajVaradwaj et al 2010 et al 2010 EgyptianEgyptian Dermatology Online Journal 6 (1Dermatology Online Journal 6 (1) ) ))

Development of psoriasis following wound Development of psoriasis following wound healinghealing..

((A)Psoriasis upon burn scar in a 74-year-old woman. (B) Epidermal A)Psoriasis upon burn scar in a 74-year-old woman. (B) Epidermal keratinocytes of psoriatic lesions show activated Stat3. Nuclei of the lesional keratinocytes of psoriatic lesions show activated Stat3. Nuclei of the lesional keratinocytes are positive for Stat3, suggesting activated status of Stat3keratinocytes are positive for Stat3, suggesting activated status of Stat3) ) SanoSano etal., Journal of Dermatological Science (2008) 50, 1—14etal., Journal of Dermatological Science (2008) 50, 1—14))

Psoriatic lesions of K5.Stat3C micePsoriatic lesions of K5.Stat3C mice

((A)Psoriasis lesions and its histology (H and E staining, A)Psoriasis lesions and its histology (H and E staining, (B).(B). (Sano(Sano etal., Journal of Dermatological Science etal., Journal of Dermatological Science (2008) 50, 1—14(2008) 50, 1—14))

A Tender Piece of InformationA Tender Piece of Information

Do Other Therapies Work Within This Do Other Therapies Work Within This Framework?Framework?

Anti–T-cell agents could affect Anti–T-cell agents could affect Th17Th17 cells as they would other T cells, but cells as they would other T cells, but this needs to be clarified this needs to be clarified

Anti-TNFAnti-TNF agents could decrease agents could decrease activity of activity of Th1Th17 cells or work directly 7 cells or work directly on keratinocyte responseson keratinocyte responses

Studies on Stat 3 in PsoriasisStudies on Stat 3 in Psoriasis

Stat 3 in PsoriasisStat 3 in Psoriasis

Manipulation of PsorasisManipulation of Psorasis

Psoriasis: New Immunologic Approaches to Psoriasis: New Immunologic Approaches to TreatmentTreatment

TNF inhibitionTNF inhibition– Antibodies to TNFAntibodies to TNF– Soluble TNF receptorsSoluble TNF receptors

Costimulatory Costimulatory blockadeblockade

Adhesion molecule Adhesion molecule inhibitioninhibition

– LFA-1LFA-1– CD2 CD2

IL-2 activation IL-2 activation blockadeblockade

Therapeutic Targets in Therapeutic Targets in Psoriasis As a T Helper 17 Psoriasis As a T Helper 17

Cell-Mediated DiseaseCell-Mediated Disease

Anti TNF approved for Anti TNF approved for psoriasis treatmentpsoriasis treatment

JEADV 2010, 24 (Suppl. 5), 2–24JEADV 2010, 24 (Suppl. 5), 2–24

IL-12/IL-23 Inhibitors in PsoriasisIL-12/IL-23 Inhibitors in Psoriasis

Kauffman et al., J Invest Dermatol 123: 1037, 2004Kauffman et al., J Invest Dermatol 123: 1037, 2004

Krueger et al., Krueger et al., N Engl J Med 356: 580, 2007 N Engl J Med 356: 580, 2007

Torti et al., J Am Acad Dermatol, Torti et al., J Am Acad Dermatol, 10.1016/j.jaad.2007.07.01610.1016/j.jaad.2007.07.016

Reviewed in Torti et al., J Am Acad Dermatol, 2007 doi: 10.1016/j.jaad.2007.07.016

IL-12/IL-23 as Therapeutic Targets IL-12/IL-23 as Therapeutic Targets in Psoriasisin Psoriasis

Role of IL-12/IL-23 in Mouse ModelsRole of IL-12/IL-23 in Mouse ModelsExperimental psoriasis is abolished by anti-p40 Ab therapyExperimental psoriasis is abolished by anti-p40 Ab therapy

Transgenic overexpression of p40 results in skin inflammationTransgenic overexpression of p40 results in skin inflammation

IL-23 injection results in skin inflammationIL-23 injection results in skin inflammation

Expression of IL-12/IL-23 in Human PsoriasisExpression of IL-12/IL-23 in Human Psoriasisp40 mRNA and protein are increased in psoriatic lesionsp40 mRNA and protein are increased in psoriatic lesions

p19 mRNA and protein are increased in psoriatic lesionsp19 mRNA and protein are increased in psoriatic lesions

IL-12 and IL-23 decrease after conventional psoriatic therapyIL-12 and IL-23 decrease after conventional psoriatic therapy

A polymorphism in p40 gene is associated with susceptibility to psoriasisA polymorphism in p40 gene is associated with susceptibility to psoriasis

Clinical Studies with anti-p40 mAbClinical Studies with anti-p40 mAb

Effect of a single 5 mg/kg dose Effect of a single 5 mg/kg dose of anti-p40 mAb in psoriasisof anti-p40 mAb in psoriasis

Kauffman et al., J Invest Dermatol 123: 1037, 2004

Current Rheumatology Reports 2007, 9:461–467

Topical Macrolactam Ascomycin Topical Macrolactam Ascomycin

Analog( Analog( ABT-281ABT-281) in Psoriasis) in Psoriasis Topical application of 3% Topical application of 3% ABT-281ABT-281 in in acetone/olive oil acetone/olive oil showedshowed its superior its superior efficacy, its rapid systemic efficacy, its rapid systemic clearance following uptake into the blood clearance following uptake into the blood stream .stream .Its ability to inhibit cytokine biosynthesis of Its ability to inhibit cytokine biosynthesis of both Th1 and Th2 cell subsets, suggests that both Th1 and Th2 cell subsets, suggests that it will have a broad therapeutic value in it will have a broad therapeutic value in inflammatory skin diseases, including inflammatory skin diseases, including psoriasis (psoriasis ( Mollison Mollison etet alal Journal of Journal of Investigative DermatologyInvestigative Dermatology ,1999, ,1999,112112, :729–, :729–738;738;).).

Future Psoriasis TherapyFuture Psoriasis Therapy((Wippel-Slupetzky&Stingl Curr Probl Dermatol., 2009, 38, : 172–189)

Future Psoriasis TherapyFuture Psoriasis Therapy((Wippel-Slupetzky&Stingl Curr Probl Dermatol., 2009, 38, : 172–189)

IL-17A blocker & early promise IL-17A blocker & early promise for psoriasisfor psoriasis

Selective inhibition of the proinflammatory cytokine Selective inhibition of the proinflammatory cytokine interleukin-17A using a novel fully human interleukin-17A using a novel fully human monoclonal antibody (AIN457) showed considerable monoclonal antibody (AIN457) showed considerable early promise for treatment of psoriasis .early promise for treatment of psoriasis .Participants were randomized to a single Participants were randomized to a single intravenous infusion of AIN457 at 3 mg/kg or intravenous infusion of AIN457 at 3 mg/kg or placebo and then followed for 12 weeks.placebo and then followed for 12 weeks.The mean decrease in PASI score 4 weeks after the The mean decrease in PASI score 4 weeks after the infusion was 58% in the AIN457-treated patients and infusion was 58% in the AIN457-treated patients and 4% with placebo4% with placebo ((B Jancin

Skin & Allergy News, , 2009 ) )

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STAT3STAT3 protein has emerged as an important determinant of protein has emerged as an important determinant of whether the naïve T cell differentiates into regulatory (whether the naïve T cell differentiates into regulatory (Treg)Treg) or or an inflammatory (an inflammatory (Th17)Th17) T cell lineage. T cell lineage. STAT3 STAT3 also has potent anti-inflammatory effects and regulates also has potent anti-inflammatory effects and regulates critical cellular processes such as, cell growth, apoptosis and critical cellular processes such as, cell growth, apoptosis and transcription of inflammatory genes. transcription of inflammatory genes. Dysregulation of Dysregulation of STAT3STAT3 pathway has therefore been implicated pathway has therefore been implicated in the development of chronic inflammatory diseases, as well in the development of chronic inflammatory diseases, as well as, a number of malignant and neurodegenerative diseases. as, a number of malignant and neurodegenerative diseases. New insights from animal models of psoriasis as an exemplar New insights from animal models of psoriasis as an exemplar of critical roles that of critical roles that STAT3STAT3 pathways play in inflammatory pathways play in inflammatory diseases including psoriasis and on how inhibiting diseases including psoriasis and on how inhibiting STAT3STAT3 can be exploited to mitigate pathogenic autoimmunity(can be exploited to mitigate pathogenic autoimmunity(Egwuagu Egwuagu Cytokine 47 (2009) 149–156Cytokine 47 (2009) 149–156))


Stat3 is Key intracellular signaling Stat3 is Key intracellular signaling molecule important in molecule important in Th17Th17 development and mediates development and mediates IL-22IL-22––induced keratinocyte hyperproliferation.induced keratinocyte hyperproliferation.

Blocking of stat3 pathway is good-to-Blocking of stat3 pathway is good-to-excellent (similar to excellent (similar to TNF-aTNF-a inhibitors): inhibitors): major signaling pathway inhibition major signaling pathway inhibition may have expected good clinical may have expected good clinical results in psoriasis .results in psoriasis .

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Stat3protein & immunocompetent cells in psoriasis pathogenesis