Inflammatory Inflammatory ResponseResponse

CytokinesCytokines Cytokines are small proteins or ____________ secreted for the Cytokines are small proteins or ____________ secreted for the

purpose of altering the function of target cells in an purpose of altering the function of target cells in an _____________, ____________, or ________ fashion._____________, ____________, or ________ fashion.

Cytokines are produced by cells individually (e.g., Cytokines are produced by cells individually (e.g., lymphocytes or macrophages) or as components of a tissue lymphocytes or macrophages) or as components of a tissue (e.g., the intestinal epithelium). (e.g., the intestinal epithelium).

Many cytokines are_____________; these cytokines are capable Many cytokines are_____________; these cytokines are capable of inducing many different biologic effects, depending on the of inducing many different biologic effects, depending on the target cell types involved and the presence or absence of target cell types involved and the presence or absence of other modulating factors. other modulating factors.

Redundancy is another characteristic feature of cytokines; Redundancy is another characteristic feature of cytokines; that is, several different cytokines can exert very similar that is, several different cytokines can exert very similar biologic effects.biologic effects.

endocrine paracrine autocrine

glycoproteins

pleiotropicpleiotropic

CytokinesCytokines Another way that cytokines can be categorized is on Another way that cytokines can be categorized is on

the basis of structure. the basis of structure.

Type IType I cytokines cytokines – are a large group of proteins that share a characteristic tertiary are a large group of proteins that share a characteristic tertiary

structure consisting of a bundle of four a helices. structure consisting of a bundle of four a helices. – The receptors for type I cytokines also share structural The receptors for type I cytokines also share structural

similarities and are referred to as similarities and are referred to as type I cytokine receptorstype I cytokine receptors. . – Type I cytokines include the following proteins: interleukin-2 Type I cytokines include the following proteins: interleukin-2

(IL-2), IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-13, IL-15, and (IL-2), IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-11, IL-13, IL-15, and granulocyte colony-stimulating factor (G-CSF).granulocyte colony-stimulating factor (G-CSF).

Type IIType II cytokines cytokines– including interferon-α (IFN-α), IFN-β, IFN-γ, and IL-10, are a including interferon-α (IFN-α), IFN-β, IFN-γ, and IL-10, are a

second structurally related group of proteins. second structurally related group of proteins.

CytokinesCytokines Yet another way of grouping cytokines is based on Yet another way of grouping cytokines is based on

the recognition that naive CD4+ T cells (TH0 cells) the recognition that naive CD4+ T cells (TH0 cells) can differentiate into either of two T helper (TH) can differentiate into either of two T helper (TH) subsets called TH1 and TH2.subsets called TH1 and TH2.

TH1 cells, responsible for directing the ___________ TH1 cells, responsible for directing the ___________ immune responses necessary for the eradication of immune responses necessary for the eradication of intracellular pathogens, favor macrophage intracellular pathogens, favor macrophage activation. activation.

TH2 cells have been implicated in the pathogenesis TH2 cells have been implicated in the pathogenesis of atopy and allergic inflammation and favor B-cell of atopy and allergic inflammation and favor B-cell growth and differentiation. growth and differentiation.

cell-mediatedcell-mediated

CytokinesCytokines TH1 cells produce IL-2, as well as the potent TH1 cells produce IL-2, as well as the potent

proinflammatory cytokines IFN-γ and lymphotoxin-α proinflammatory cytokines IFN-γ and lymphotoxin-α (LT-α). (LT-α).

TH2 cells produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. TH2 cells produce IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13.

TH1 cytokines are often viewed as being TH1 cytokines are often viewed as being proinflammatory, whereas TH2 cytokines are thought proinflammatory, whereas TH2 cytokines are thought of as being anti-inflammatory. of as being anti-inflammatory.

What cytokine predominantly drives TH1 differentiation?

What cytokine predominantly induces TH2 differentiation?

IL-12

IL-4

CytokinesCytokines _____________ are a special family of cytokines that consist of small _____________ are a special family of cytokines that consist of small

proteins with molecular weights in the range of 8 to 11 kd and proteins with molecular weights in the range of 8 to 11 kd and have as their primary biologic activity the have as their primary biologic activity the ability to act as ability to act as chemoattractants for leukocytes or fibroblastschemoattractants for leukocytes or fibroblasts. .

Another cytokine subclass is a group of proteins that Another cytokine subclass is a group of proteins that act primarily act primarily to stimulateto stimulate the growth or differentiation (or both) the growth or differentiation (or both) of of hematopoietic progenitor cellshematopoietic progenitor cells; these mediators are collectively ; these mediators are collectively referred to as ________________________.referred to as ________________________.

Other growth and differentiation factors, including the various Other growth and differentiation factors, including the various platelet-derived growth factors, epidermal growth factor, and platelet-derived growth factors, epidermal growth factor, and keratinocyte growth factorkeratinocyte growth factor, also fit into the broad category of , also fit into the broad category of cytokines.cytokines.

ChemokinesChemokines

colony-stimulating factors.colony-stimulating factors.

The immune response to infection has two broad The immune response to infection has two broad components. components.

Moving along..Moving along..

which which occur early and are not antigen specificoccur early and are not antigen specific, depend , depend largely on proper functioning of largely on proper functioning of natural killer (NK) cells natural killer (NK) cells and phagocytic cells, such as monocytes, macrophages, and and phagocytic cells, such as monocytes, macrophages, and neutrophils. neutrophils.

which develop which develop later after antigen processinglater after antigen processing and the and the clonal expansion of T- and B-cell subsets, are clonal expansion of T- and B-cell subsets, are antigen antigen specificspecific. .

InnateInnate responsesresponses..

AcquiredAcquired responses responses

A number of cytokines, including transforming growth factor-β A number of cytokines, including transforming growth factor-β (TGF-β), tumor necrosis factor (TNF), IL-1, IL-6, IL-10, IL-12, and IL-(TGF-β), tumor necrosis factor (TNF), IL-1, IL-6, IL-10, IL-12, and IL-18, are synthesized by cells of the innate immune system and 18, are synthesized by cells of the innate immune system and contribute to the ability of the host to mount an early, innate contribute to the ability of the host to mount an early, innate immune response to an infectious challengeimmune response to an infectious challenge. Another group of . Another group of cytokines, cytokines, the interferonsthe interferons, are also key components of the innate , are also key components of the innate immune systemimmune system

•????? responses

??????? responses

InterferonInterferon The The interferons,interferons, named for their ability to named for their ability to

interfere with viral infection, were initially interfere with viral infection, were initially discovered in the 1950s as soluble factors discovered in the 1950s as soluble factors secreted by leukocytes. secreted by leukocytes.

The type 1 interferons, The type 1 interferons, IFN-α and IFN-β,IFN-α and IFN-β, are are primarily involved as mediators of innate primarily involved as mediators of innate immune responses to viral infection.immune responses to viral infection.

IFN-γIFN-γ, though also important in the immune , though also important in the immune response to viral infection, has much broader response to viral infection, has much broader activity as a proinflammatory mediator.activity as a proinflammatory mediator.

IFN-γIFN-γ IFN-γ is produced by three types of cells: IFN-γ is produced by three types of cells:

– CD4+ TH1 cells, CD4+ TH1 cells, – CD8+ TH1 cellsCD8+ TH1 cells– and NK cells.and NK cells.

IFN-γ, along with two other cytokines, IL-12 IFN-γ, along with two other cytokines, IL-12 and IL-18, plays a critical role in promoting and IL-18, plays a critical role in promoting the differentiation of CD4+ T cells to the the differentiation of CD4+ T cells to the TH1 phenotype.TH1 phenotype.

Because TH1 cells also produce IFN-γ, the Because TH1 cells also produce IFN-γ, the potential exists for a positive feedback potential exists for a positive feedback loop. loop.

IFN-γIFN-γ IFN-γ inhibits the differentiation of IFN-γ inhibits the differentiation of

lymphocytes into cells with the TH2 lymphocytes into cells with the TH2 phenotype.phenotype.

TH2 cells secrete the counter-TH2 cells secrete the counter-regulatory cytokines:regulatory cytokines:– IL-4 and IL-10IL-4 and IL-10

Effect of IFN-γ to down-regulate the Effect of IFN-γ to down-regulate the production of these cytokines by TH2 production of these cytokines by TH2 cells promotes the development of an cells promotes the development of an inflammatory response to an invading inflammatory response to an invading pathogen. pathogen.

IFN-γIFN-γ When responsive target cells are When responsive target cells are

exposed to IFN-γ, a number of genes are exposed to IFN-γ, a number of genes are activated within minutesactivated within minutes

IFN-γ–induced signal transduction occurs IFN-γ–induced signal transduction occurs through the activation of a protein through the activation of a protein tyrosine phosphorylation cascade known tyrosine phosphorylation cascade known as the as the JAK-STAT pathwayJAK-STAT pathway

JAK initially stood for JAK initially stood for ________________________________ __ because the biologic role of these because the biologic role of these proteins was not established when they proteins was not established when they were initially discovered.were initially discovered.

Because these receptor-associated Because these receptor-associated kinases look both outside and inside the kinases look both outside and inside the cell, JAK has now come to stand for cell, JAK has now come to stand for Janus Janus kinases,kinases, after _______________________ after _______________________

jjust ust aanother nother kkinaseinase

the two-faced Roman god.the two-faced Roman god.

NADPH oxidaseNADPH oxidase

IFN-γIFN-γ Prophylactic treatment with Prophylactic treatment with recombinant recombinant

IFN-γIFN-γ has been shown to markedly has been shown to markedly reduce reduce the frequency of infectionsthe frequency of infections in patients with in patients with chronic granulomatous disease,achronic granulomatous disease,a life- life-threatening condition caused by an threatening condition caused by an inherited defect in _______________inherited defect in _______________, the , the enzyme complex responsible for generating enzyme complex responsible for generating reactive ________ species in phagocytes. reactive ________ species in phagocytes.

Three major clinical trialsThree major clinical trials of prophylactic of prophylactic IFN-γ treatment were conducted in patients IFN-γ treatment were conducted in patients with multiple with multiple trauma or major thermal trauma or major thermal injuryinjury. Unfortunately, in all three studies, . Unfortunately, in all three studies, the incidence of infection and the incidence of infection and mortality was mortality was similar in cytokine- and placebo-treated similar in cytokine- and placebo-treated patients.patients.

oxygenoxygen

INTERLEUKIN-1 AND TUMOR NECROSIS INTERLEUKIN-1 AND TUMOR NECROSIS FACTOR FACTOR

IL-1 and TNF are structurally IL-1 and TNF are structurally dissimilar pluripotent cytokines. dissimilar pluripotent cytokines.

Although these compounds bind to Although these compounds bind to different cellular receptors, their different cellular receptors, their multiple biologic activities overlapmultiple biologic activities overlap considerablyconsiderably

Through their ability to potentiate Through their ability to potentiate the the activation of helper T cellsactivation of helper T cells, IL-1 , IL-1 and TNF can and TNF can promote nearly all promote nearly all types of humoral and cellular types of humoral and cellular immune responsesimmune responses

Both these cytokines are capable of Both these cytokines are capable of activating neutrophils and activating neutrophils and macrophagesmacrophages and and inducininducing the g the expression of expression of many other cytokinesmany other cytokines and inflammatory mediators. and inflammatory mediators.

EffectEffect IL-1IL-1 TNFTNFFeverFever

HeadacheHeadache

AnorexiaAnorexia

NeutrophiliaNeutrophilia

Increased platelet Increased platelet countcount

Activation of Activation of coagulation cascadecoagulation cascade

Pulmonary edemaPulmonary edema

HypercortisolemiaHypercortisolemia

Systemic arterial Systemic arterial hypotensionhypotension

+ +

+ +

+ +

+ +

+ -

- +

- +

+ +

+ +

Interleukin-1Interleukin-1

IL-1RAIL-1RA, the third member of the IL-1 family of proteins, , the third member of the IL-1 family of proteins, is biologically inactive but competes with IL-1α and IL-1β is biologically inactive but competes with IL-1α and IL-1β for binding to IL-1 receptors on cells and thereby for binding to IL-1 receptors on cells and thereby functions as a competitive inhibitor to limit IL-1–functions as a competitive inhibitor to limit IL-1–mediated effects.mediated effects.

IL-1 was first described as a IL-1 was first described as a lymphocyte-activating factorlymphocyte-activating factor produced produced by stimulated macrophages.by stimulated macrophages.

IL-1 is not a single compound, but rather IL-1 is not a single compound, but rather a a family of three distinct proteins:family of three distinct proteins:

IL-1α, IL-1β, and IL-1 receptor IL-1α, IL-1β, and IL-1 receptor antagonist (IL-RA)antagonist (IL-RA) , which are products , which are products of different genes located close to one of different genes located close to one another on the long arm of human another on the long arm of human chromosome 2.chromosome 2.

Name Them!!!!!

IL-1IL-1 IL-1 is synthesized by a wide variety of cell IL-1 is synthesized by a wide variety of cell

types, including :types, including :– MonocytesMonocytes– MacrophagesMacrophages– B lymphocytesB lymphocytes– T lymphocytesT lymphocytes– NK cells, NK cells, – KeratinocytesKeratinocytes– dendritic cellsdendritic cells– FibroblastsFibroblasts– NeutrophilNeutrophil– endothelial cellsendothelial cells– enterocytes. enterocytes.

Name One !!!!!

IL-1IL-1

Compounds that can trigger the Compounds that can trigger the production of by monocytes, production of by monocytes, macrophages, or other cell types macrophages, or other cell types include microbial cell wall products, include microbial cell wall products, such as :such as :– lipopolysaccharide (LPS)lipopolysaccharide (LPS)– lipoteichoic acidlipoteichoic acid– zymosan zymosan

gram-negative bacteriagram-negative bacteria

gram-positive bacteriagram-positive bacteriayeastyeast

IL-1RAIL-1RA In some tissues, such as intestinal In some tissues, such as intestinal

epithelium, the formation of epithelium, the formation of intracellular intracellular IL-1RA may serve a IL-1RA may serve a counter-regulatory function to counter-regulatory function to limit inflammationlimit inflammation and thereby and thereby confer mucosal protection.confer mucosal protection.

Moreover, an Moreover, an imbalance betweenimbalance between the production of the production of IL-1 and IL-1RAIL-1 and IL-1RA may promote the development of may promote the development of chronic inflammationchronic inflammation in certain in certain pathologic conditions such as pathologic conditions such as Crohn's diseaseCrohn's disease

IL-1 receptorsIL-1 receptors

IL-1RI is an 80-kd transmembrane protein with a long cytoplasmic tail.

IL-1RI is present on a wide variety of cell types, including T cells, endothelial cells, hepatocytes, and fibroblasts.

IL-1RII is actually a decoy receptor that serves a counter-regulatory role by competing with IL-1RI, the fully functional IL-1 receptor, for IL-1 in the extracellular space.

IL-1RII is the predominant IL-1 receptor found on B cells, monocytes, and neutrophils.

The extracellular domains of IL-1RI and IL-1RII are shed by The extracellular domains of IL-1RI and IL-1RII are shed by activated neutrophils and monocytes. activated neutrophils and monocytes.

The shed receptors can act as a sink for secreted IL-1 and, The shed receptors can act as a sink for secreted IL-1 and, thus, along with IL-1RA, represent an important counter-thus, along with IL-1RA, represent an important counter-regulatory component of the inflammatory response.regulatory component of the inflammatory response.

There are two distinct IL-1 receptors, There are two distinct IL-1 receptors, IL-1RIIL-1RI and and IL-1RIIIL-1RII

Moving along……Moving along…… Three major anticoagulant pathways exist and all Three major anticoagulant pathways exist and all

can be inhibited by the inflammatory cascade: can be inhibited by the inflammatory cascade: – antithrombin, antithrombin, – protein C system,protein C system,– TF pathway inhibitor. TF pathway inhibitor.

Antithrombin is a serine protease inhibitor that Antithrombin is a serine protease inhibitor that antagonizes thrombin and factor Xa. antagonizes thrombin and factor Xa.

During severe inflammatory responses, During severe inflammatory responses, antithrombin levels are markedly decreased as antithrombin levels are markedly decreased as the result of consumption, impaired synthesis the result of consumption, impaired synthesis (negative acute phase response), and (negative acute phase response), and degradation by elastase from activated degradation by elastase from activated neutrophils.neutrophils.

Protein CProtein C Protein C is activated by thrombin bound to thrombomodulin. Protein C is activated by thrombin bound to thrombomodulin.

During systemic inflammation, protein C levels are reduced During systemic inflammation, protein C levels are reduced because of impaired synthesis and degradation by neutrophil because of impaired synthesis and degradation by neutrophil elastase.elastase.

The protein C system is inhibited by decreased expression of The protein C system is inhibited by decreased expression of

thrombomodulin induced by TNF and IL-1β.thrombomodulin induced by TNF and IL-1β.

In addition to its role in regulating coagulation, the protein C In addition to its role in regulating coagulation, the protein C system also modulates the inflammatory response.system also modulates the inflammatory response.

Activated protein C binds to the endothelial protein C Activated protein C binds to the endothelial protein C receptor. receptor.

Activation of this signaling pathway inhibits inhibits secretion Activation of this signaling pathway inhibits inhibits secretion of TNF, IL-1β, IL-6, and IL-8 by monocytes.of TNF, IL-1β, IL-6, and IL-8 by monocytes.

Circulating levels of protein C decrease in patients with severe Circulating levels of protein C decrease in patients with severe sepsis or septic shock, and a sepsis or septic shock, and a marked deficiency of protein C in marked deficiency of protein C in these patients is a prognostic indicator for an unfavorable these patients is a prognostic indicator for an unfavorable outcome.outcome.

Various strategies to inhibit excessive activation of the Various strategies to inhibit excessive activation of the coagulation system were extensively evaluated both in animal coagulation system were extensively evaluated both in animal models of endotoxemia and sepsis and in clinical trials. models of endotoxemia and sepsis and in clinical trials.

One of these approaches, the administration of recombinant One of these approaches, the administration of recombinant human activated protein C, also called human activated protein C, also called drotrecogin alfa drotrecogin alfa (activated),(activated), was shown in a large multicentric randomized was shown in a large multicentric randomized clinical trial to significantly clinical trial to significantly improve survival in patients with improve survival in patients with severe sepsis. severe sepsis.

(Understandably, bleeding complications can occur with the use of (Understandably, bleeding complications can occur with the use of drotrecogin alfa (activated). Furthermore, this agent was not beneficial drotrecogin alfa (activated). Furthermore, this agent was not beneficial for septic patients with an Acute Physiology and Chronic Health for septic patients with an Acute Physiology and Chronic Health Evaluation II (APACHE II) score lower than 25, postoperative patients Evaluation II (APACHE II) score lower than 25, postoperative patients with single–organ system dysfunction,or pediatric patients with severe with single–organ system dysfunction,or pediatric patients with severe sepsis.)sepsis.)

INTERLEUKIN-6INTERLEUKIN-6

IL-6 is a pluripotent cytokine intimately associated IL-6 is a pluripotent cytokine intimately associated with the inflammatory response to injury or with the inflammatory response to injury or infection.infection.

IL-6 can be produced not only by immunocytes (e.g., IL-6 can be produced not only by immunocytes (e.g., monocytes, macrophages, and lymphocytes) but also monocytes, macrophages, and lymphocytes) but also by many other cell types, including endothelial cells by many other cell types, including endothelial cells and intestinal epithelial cells. and intestinal epithelial cells.

Factors known to induce expression of IL-6 include Factors known to induce expression of IL-6 include IL-1, TNF, platelet-activating factor, LPS, and IL-1, TNF, platelet-activating factor, LPS, and reactive oxygen metabolites. reactive oxygen metabolites.

IL-6IL-6 The cellular and physiologic effects of IL-6 The cellular and physiologic effects of IL-6

are diverse and include are diverse and include – induction of fever, induction of fever, – promotion of B-cell maturation and differentiationpromotion of B-cell maturation and differentiation– stimulation of T-cell proliferation and stimulation of T-cell proliferation and

differentiationdifferentiation– promotion of differentiation of nerve cellspromotion of differentiation of nerve cells– stimulation of the hypothalamic-pituitary-adrenal stimulation of the hypothalamic-pituitary-adrenal

axis, axis, – induction of the synthesis of acute phase proteins induction of the synthesis of acute phase proteins

(e.g., C-reactive protein) by hepatocytes.(e.g., C-reactive protein) by hepatocytes.

Name One !!!!!

IL-6IL-6 Circulating concentrations of IL-6 increase Circulating concentrations of IL-6 increase

dramatically after tissue injury.dramatically after tissue injury.

Elevated plasma levels of IL-6 are Elevated plasma levels of IL-6 are consistently observed in patients with consistently observed in patients with sepsis or septic shock. sepsis or septic shock.

The degree to which circulating IL-6 levels The degree to which circulating IL-6 levels are elevated after tissue trauma or during are elevated after tissue trauma or during sepsis has been shown to correlate with the sepsis has been shown to correlate with the risk for postinjury complications or death. risk for postinjury complications or death.

INTERLEUKIN-11INTERLEUKIN-11 IL-11 is expressed in a variety of cell types, IL-11 is expressed in a variety of cell types,

including neurons, fibroblasts, and including neurons, fibroblasts, and epithelial cells. epithelial cells.

Expression of IL-11 can be Expression of IL-11 can be up-regulated by up-regulated by IL-1, TGF-βIL-1, TGF-β, and other cytokines or growth , and other cytokines or growth factors. factors.

From a functional standpoint, IL-11 is a From a functional standpoint, IL-11 is a hematopoietic growth factorhematopoietic growth factor with particular with particular activity as a stimulator of activity as a stimulator of megakaryocytopoiesis and thrombopoiesis. megakaryocytopoiesis and thrombopoiesis.

IL-11IL-11

Circulating levels of IL-11 Circulating levels of IL-11 increase inincrease in patients with DIC and patients with DIC and sepsissepsis. .

IV or oral administration of IV or oral administration of recombinant IL-11 improves survival recombinant IL-11 improves survival in neutropenic rodents with sepsis, in neutropenic rodents with sepsis, possibly by possibly by preserving preserving the integrity the integrity of the of the intestinal mucosal barrierintestinal mucosal barrier

INTERLEUKIN-8 AND OTHER INTERLEUKIN-8 AND OTHER CHEMOKINESCHEMOKINES

________________________ is the term used to denote the is the term used to denote the directed migration of cells toward directed migration of cells toward increasing concentrations of an activating increasing concentrations of an activating substance. substance.

The ability to recruit leukocytes to an The ability to recruit leukocytes to an inflammatory focus by promoting inflammatory focus by promoting chemotaxis is the primary biologic activity chemotaxis is the primary biologic activity of a special group of cytokines called of a special group of cytokines called __________.__________.

ChemotaxisChemotaxis

chemokineschemokines

ChemokinesChemokines Four chemokine subgroups have been described. Four chemokine subgroups have been described.

The subgroups are defined by the degree of The subgroups are defined by the degree of separation of the first two NH2-terminal cysteine separation of the first two NH2-terminal cysteine residues.residues.

– CXC or α-chemokines, the first two cysteine moieties CXC or α-chemokines, the first two cysteine moieties are separated by a single nonconserved amino acid are separated by a single nonconserved amino acid residue,residue,

– CC or β-chemokines, the NH2-terminal cysteines are CC or β-chemokines, the NH2-terminal cysteines are directly adjacent to each other. directly adjacent to each other.

– C chemokine subgroup is characterized by the C chemokine subgroup is characterized by the presence of only a single NH2-terminal cysteine presence of only a single NH2-terminal cysteine moiety. moiety.

– CX3C subgroup has only one member (fractalkine); in CX3C subgroup has only one member (fractalkine); in this chemokine, the NH2-terminal cysteine residues this chemokine, the NH2-terminal cysteine residues are separated by three intervening amino acids.are separated by three intervening amino acids.

Name them !!!!!!!

IL-8IL-8 IncreasedIncreased circulating concentrations of IL-8 were detected circulating concentrations of IL-8 were detected

in experimental animal models of infection or endotoxemia in experimental animal models of infection or endotoxemia and in patients and in patients with sepsis.with sepsis.

Treatment of experimental animals with Treatment of experimental animals with antibodies against antibodies against IL-8IL-8 improves survivalimproves survival or prevents pulmonary injury in or prevents pulmonary injury in models of sepsis or ischemia/reperfusion injury.models of sepsis or ischemia/reperfusion injury.

These observations support the view that These observations support the view that IL-8–mediated IL-8–mediated activationactivation of neutrophilsof neutrophils plays an important role in the plays an important role in the pathogenesis of pathogenesis of organ system damageorgan system damage in these syndromes. in these syndromes.

INTERLEUKIN-12INTERLEUKIN-12

produced primarily by produced primarily by antigen-presenting cells antigen-presenting cells

IL-12 receptor is IL-12 receptor is expressed on T cells and NK expressed on T cells and NK cells.cells.

The most important biologic activity associated The most important biologic activity associated with IL-12 is to with IL-12 is to promote TH1 responses by helper promote TH1 responses by helper T cellsT cells. .

In this regard, IL-12 promotes the differentiation In this regard, IL-12 promotes the differentiation of naive T cells into TH1 cells capable of of naive T cells into TH1 cells capable of producing IFN-γ after activationproducing IFN-γ after activation

INTERLEUKIN-12INTERLEUKIN-12 IL-12 has also been IL-12 has also been implicated in the pathogenesis implicated in the pathogenesis

of IBDof IBD. T cells eluted from the lamina propria of . T cells eluted from the lamina propria of intestinal resection specimens from patients with intestinal resection specimens from patients with Crohn's disease secrete cytokines consistent with a Crohn's disease secrete cytokines consistent with a TH1-like profile.TH1-like profile.

When When antibodies to IL-12antibodies to IL-12 are administered to mice are administered to mice with with fecal peritonitisfecal peritonitis induced by cecal ligation and induced by cecal ligation and perforation, perforation, mortality is increasedmortality is increased and clearance of and clearance of the bacterial load is impaired.the bacterial load is impaired.

Conversely, pretreatment or even post-treatment Conversely, pretreatment or even post-treatment with with recombinant IL-12recombinant IL-12 has been shown to has been shown to improve improve survivalsurvival in a in a murine model of bacterial peritonitismurine model of bacterial peritonitis

INTERLEUKIN-18INTERLEUKIN-18

IL-18 is structurally related to IL-1β and is functionally a IL-18 is structurally related to IL-1β and is functionally a member of the TH1-inducing family of cytokines.member of the TH1-inducing family of cytokines.

Like IL-1β, IL-18 is translated in the form of a Like IL-1β, IL-18 is translated in the form of a precursor precursor proteinprotein (pro–IL-18). (pro–IL-18).

This precursor molecule requires cleavage by the same This precursor molecule requires cleavage by the same converting enzyme that activates IL-1β (i.e., ICE) to form converting enzyme that activates IL-1β (i.e., ICE) to form biologically active IL-18. biologically active IL-18.

The two cytokines, IL-1β and IL-18, are also similar with The two cytokines, IL-1β and IL-18, are also similar with respect to the way that intracellular signaling occurs after respect to the way that intracellular signaling occurs after association of the cytokine with its receptor on target cells. association of the cytokine with its receptor on target cells.

INTERLEUKIN-18INTERLEUKIN-18

The The main biologic activitymain biologic activity of IL-18 is to induce of IL-18 is to induce production of IFN-γ by T cells and NK cells. production of IFN-γ by T cells and NK cells.

In this regard, IL-18 acts most potently as a In this regard, IL-18 acts most potently as a co-co-stimulant in combination with IL-12. stimulant in combination with IL-12.

IL-12–induced IFN-γ expression appears to IL-12–induced IFN-γ expression appears to depend on the presence of IL-18 depend on the presence of IL-18

Circulating concentrations of IL-18 are higher in Circulating concentrations of IL-18 are higher in patients with sepsis than in those with just patients with sepsis than in those with just injuries, and injuries, and high levels of this cytokinehigh levels of this cytokine are are associated with a associated with a fatal outcome in patients with fatal outcome in patients with postoperative sepsispostoperative sepsis

INTERLEUKIN-4, INTERLEUKIN-10, AND INTERLEUKIN-4, INTERLEUKIN-10, AND

INTERLEUKIN-13INTERLEUKIN-13 Can all be regarded as Can all be regarded as inhibitory, anti-inhibitory, anti-

inflammatory,inflammatory, or or counter-regulatorycounter-regulatory cytokines. cytokines.

All three of these cytokines are All three of these cytokines are produced by produced by TH2 cells TH2 cells

serve to serve to modulate the productionmodulate the production and effects and effects of proinflammatory cytokines such as of proinflammatory cytokines such as TNF and TNF and IL-1.IL-1.

IL-4IL-4 IL-4, originally described as a B-cell growth factor, is a IL-4, originally described as a B-cell growth factor, is a

15- to 20-kd glycoprotein that is synthesized by 15- to 20-kd glycoprotein that is synthesized by – TH2 cellsTH2 cells– mast cellsmast cells– basophilsbasophils– eosinophils. eosinophils.

IL-4 has many biologic actions that promote IL-4 has many biologic actions that promote expression of the TH2 phenotype;expression of the TH2 phenotype;– down-regulation of proinflammatory and cell-mediated down-regulation of proinflammatory and cell-mediated

immune responses immune responses – up-regulation of humoral (B-cell–mediated) immune up-regulation of humoral (B-cell–mediated) immune

responses. responses.

IL-4IL-4 induces differentiation of induces differentiation of CD4+ T cells into CD4+ T cells into

TH2 cellsTH2 cells

conversely, conversely, down-regulates differentiation down-regulates differentiation of CD4+ T cells into TH1 cells. of CD4+ T cells into TH1 cells.

inhibitsinhibits the production of the production of TNF, IL-1, IL-8, TNF, IL-1, IL-8, and PGE2and PGE2 by stimulated monocytes or by stimulated monocytes or macrophagesmacrophages

IL-4 acts as a comitogen for B cells and IL-4 acts as a comitogen for B cells and promotes expression of the class II major promotes expression of the class II major histocompatibility complex (MHC) on B histocompatibility complex (MHC) on B cells.cells.

IL-10IL-10

originally called originally called cytokine synthesis inhibitory cytokine synthesis inhibitory factor,factor, was first isolated from supernatants was first isolated from supernatants of cultures of activated T cells.of cultures of activated T cells.

produced primarily by TH2 cellsproduced primarily by TH2 cells, but it is also , but it is also released by activated monocytes released by activated monocytes

IL-10 acts to IL-10 acts to down-regulate the down-regulate the inflammatoryinflammatory responseresponse through numerous through numerous mechanisms. mechanisms.

IL-10IL-10

Administering exogenous IL-10 in an Administering exogenous IL-10 in an effort to blunt excessive effort to blunt excessive inflammation has led to inflammation has led to mixed mixed results in experimental modelsresults in experimental models of of sepsis or septic shock. sepsis or septic shock.

IL-13IL-13 IL-13 is 12-kd protein IL-13 is 12-kd protein closely related to IL-4.closely related to IL-4. The two proteins have about 25% homology and The two proteins have about 25% homology and

share many structural characteristics.share many structural characteristics. IL-13 is IL-13 is produced by TH2 cellsproduced by TH2 cells and also and also

undifferentiated CD4+ T cells and CD8+ T cells. undifferentiated CD4+ T cells and CD8+ T cells. Binding of either IL-4 or IL-13 to their respective Binding of either IL-4 or IL-13 to their respective

receptors induces signaling by activating the same receptors induces signaling by activating the same JAK kinases, JAK1 and Tyk2.JAK kinases, JAK1 and Tyk2.

does does nonot have any direct t have any direct affects on T cells.affects on T cells. down-regulatesdown-regulates the production of the production of proinflammatory proinflammatory

cytokines cytokines increasesincreases the production of the production of anti-inflammatory anti-inflammatory

proteinsproteins

IL-13IL-13

Additional anti-inflammatory Additional anti-inflammatory properties of IL-13 include inhibition properties of IL-13 include inhibition of induction of the enzyme COX-2of induction of the enzyme COX-2– required for the production of required for the production of

prostaglandins, and induction of an prostaglandins, and induction of an enzyme, 15-lipoxygenase, that catalyzes enzyme, 15-lipoxygenase, that catalyzes the formation of a lipid mediator (lipoxin the formation of a lipid mediator (lipoxin A4) with A4) with anti-inflammatory properties. anti-inflammatory properties.

EICOSANOIDS EICOSANOIDS

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COX1/COX2COX1/COX2

COX-2, however, is an COX-2, however, is an inducible enzymeinducible enzyme. . Expression of COX-2 is Expression of COX-2 is induced byinduced by a number of a number of stimuli, including various stimuli, including various growth factors and growth factors and proinflammatory proinflammatory

cytokinescytokines..

COX-1 is COX-1 is expressed expressed constitutivelyconstitutively in a in a variety of tissues, and variety of tissues, and mediators produced by mediators produced by this isoform are thought this isoform are thought to be important in to be important in various homeostatic various homeostatic processes, such as processes, such as regulating renal regulating renal perfusionperfusion and and salt and salt and water handlingwater handling, , maintaining hemostasis maintaining hemostasis by modulating platelet by modulating platelet aggregation, and aggregation, and preserving preserving gastrointestinal mucosal gastrointestinal mucosal integrity.integrity.

identification of COX-2 as the so-called inflammatory identification of COX-2 as the so-called inflammatory isoform of cyclooxygenase led to intense efforts to develop isoform of cyclooxygenase led to intense efforts to develop drugs selective for the inducible enzyme. drugs selective for the inducible enzyme.

Selective COX-2 inhibitors were initially widely prescribed Selective COX-2 inhibitors were initially widely prescribed by clinicians. by clinicians.

However, data from large multicentric trials of rofecoxib, However, data from large multicentric trials of rofecoxib, one of the compounds in this class, showed that treatment one of the compounds in this class, showed that treatment with this agent was associated with an with this agent was associated with an increased risk for increased risk for death from cardiovascular complications.death from cardiovascular complications.

As a result of these findings, As a result of these findings, rofecoxib was withdrawn from rofecoxib was withdrawn from the market. the market.

Many of the downstream actions of the proinflammatory cytokines Many of the downstream actions of the proinflammatory cytokines occur as a result of increased expression of two key enzymes, iNOS occur as a result of increased expression of two key enzymes, iNOS

and COX-2. and COX-2.

iNOS is one of three isoforms of iNOS is one of three isoforms of an enzyme, nitric oxide synthase an enzyme, nitric oxide synthase (NOS), that catalyzes conversion (NOS), that catalyzes conversion of the amino acid l-arginine to the of the amino acid l-arginine to the free radical gas NOfree radical gas NO

produced by many different types produced by many different types of cells and serves as both a of cells and serves as both a signaling and an effector molecule signaling and an effector molecule in mammalian biology.in mammalian biology.

NOS-1 (also called NOS-1 (also called neuronal NOSneuronal NOS or or nNOSnNOS) and NOS-3 (also called ) and NOS-3 (also called endothelialendothelial or or eNOSeNOS) tend to be ) tend to be expressed constitutively in expressed constitutively in various cell types, various cell types,

iNOS is expressed for the most iNOS is expressed for the most part only after stimulation of cells part only after stimulation of cells by proinflammatory cytokinesby proinflammatory cytokines (particularly IFN-γ, TNF, and IL-1) (particularly IFN-γ, TNF, and IL-1) or LPS. or LPS.

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NONO NOS-1 and NOS-2 produce small puffs of NONOS-1 and NOS-2 produce small puffs of NO· in response to transient · in response to transient

changes in the intracellular ionized calcium concentration. changes in the intracellular ionized calcium concentration.

In contrast,In contrast, iNOS iNOS, once induced, produces , once induced, produces large quantities of NO· for large quantities of NO· for a prolonged perioda prolonged period

Many of the biologic actions of NO·, including Many of the biologic actions of NO·, including vasodilationvasodilation, induction , induction of of vascular hyperpermeabilityvascular hyperpermeability, and , and inhibition of platelet aggregationinhibition of platelet aggregation, , are mediated through activation of the enzyme soluble guanylyl are mediated through activation of the enzyme soluble guanylyl cyclase (sGC).cyclase (sGC).

In addition, NO· In addition, NO· reacts rapidly withreacts rapidly with another another free radical, superoxide free radical, superoxide anion (O2-anion (O2-·), to form ·), to form peroxynitrite anion (ONOO-peroxynitrite anion (ONOO-), the conjugate base ), the conjugate base of the weak acid peroxynitrous acid (ONOOHof the weak acid peroxynitrous acid (ONOOH

Being a potent oxidizing and nitrosating agent, Being a potent oxidizing and nitrosating agent, ONOO-ONOO-/ONOOH is /ONOOH is thought to be thought to be responsible for many of the toxic effects of NOresponsible for many of the toxic effects of NO

ONOO-/ONOOH is capable of ONOO-/ONOOH is capable of oxidizing sulfhydryl groups on various oxidizing sulfhydryl groups on various proteinsproteins at a rapid rate, at a rapid rate, peroxidizing membrane lipids, and peroxidizing membrane lipids, and inactivating mitochondrial aconitaseinactivating mitochondrial aconitase

Heat Shock ProteinsHeat Shock Proteins

The heat shock proteins were first identified as a The heat shock proteins were first identified as a family of proteins that are family of proteins that are induced wheninduced when cells or cells or experimental animals are subjected to experimental animals are subjected to sublethal sublethal thermal stressthermal stress. .

These proteins are also These proteins are also induced byinduced by many other many other stimuli, such as stimuli, such as inflammation, oxidative stress, inflammation, oxidative stress, and infection. and infection.

The The primary roleprimary role of heat shock proteins is to of heat shock proteins is to serve as serve as molecular chaperones to facilitate the molecular chaperones to facilitate the proper folding of nascent proteins.proper folding of nascent proteins.

Heat Shock ProteinsHeat Shock Proteins normally found inside cells, but under certain normally found inside cells, but under certain

conditions these proteins can be detected in conditions these proteins can be detected in the extracellular milieu.the extracellular milieu.– For example, elevated circulating levels of HSP70 For example, elevated circulating levels of HSP70

have been found in trauma patients and patients have been found in trauma patients and patients in the immediate period after coronary artery in the immediate period after coronary artery bypass graft surgery.bypass graft surgery.

these proteins may serve as these proteins may serve as endogenous endogenous danger signalsdanger signals and and trigger activation of the trigger activation of the inflammatoryinflammatory responseresponse after damage to after damage to tissues.tissues.

The EndThe End