View
213
Download
0
Category
Preview:
Citation preview
Cytokines and signaling pathways inhealthy and disease
DENT516
Ge Jin, Ph.D.Email: ge.jin@case.eduPhone: 3683791Office: DO3570, School of Dental Medicine
March 26, 2012
Learning Objectives:
1. What are cytokines?
2. understand that NFB and STAT proteins are transcription factors that modulate immune responses
3. understand that cytokines play important roles in PD
Immune cells and the mediators they produce
Cytokines
small, secreted, non-antibody proteins
produced by cells involved in both innate & adaptive immunity
mediate and regulate immunity, inflammation, and hematopoiesis
Cytokines Lymphokine: made by activated lymphocytes, especially TH cells, e.g. IL-2
Monokine: made by mononuclear phagocytes, e.g. Mig/CXCL9
Chemokine: chemotactic activity, e.g. IL-8, CXCL12
Interleukin: interaction between leukocytes IL-1, IL-8, IL-10, IL-13……
named by activity: Tumor Necrosis Factor (TNF), Colony Stimulation Factor (CSF), Transforming Growth Factor (TGF)….
Properties of Cytokines
produced in response to immune stimuli -- not store pre-formed -- synthesis: DNA mRNA protein secretion -- slow cellular response
can act on the cells that produce them (autocrine action)
can act on nearby cells (paracrine action)
can act on distance cells (endocrine action)
Properties of Cytokines
can be produced by many cell types and act on many cell types (pleiotropic)
different cytokines can have similar actions (redundant)
Properties of Cytokines
can modulate synthesis of other cytokines - cascades: e.g. TNF IL-1 IL-6, IL-8…
- enhance or suppress production of other cytokines: positive or negative
influence the action of other cytokines - antagonistic - additive - synergistic
short half life, low plasma concentration, bind to receptor with high affinity
Immunoglobulin superfamily: IL1R, TLRs…
Cytokine Receptors(grouped by structures into families)
Toll-IL-1 Receptordomain (TIR)
Toll-likereceptors (TLRs)
leucine-richrepeatsimmunoglobulin
domain
IL-1 receptor
cell membrane
TNFR family: TNF, FasL, CD40L…
Cytokine Receptors
Cytokine ReceptorsG
M-C
SF
R
IL-3
R
IL-5
R
GM-CSF
IL-2
IL-3 IL-5
IL-15 IL-7 IL-9
IL-2
R
IL-2
IL-1
5R
IL-2
IL-7
R
IL-9
R
class I receptor family: hematopoietin family
gp130gp130 gp130 gp130
CN
TF
R
cell membrane cell membrane
GM-CSF: Granulocyte macrophage colony-stimulating factorIL: interleukingp130: glycoprotein 130 (m.w. 130 kDa)
IL-6 IL-11
CNTF LIF/OSM
-- share receptors
-- defect in a unique cytokine have little effect
-- defect in a share component (common receptor) can have profound effects
e.g. IL-2R defect X- linked SCID
(Severe Combined Immunodeficiency)
class II receptor family: Interferon , , and
Cytokine Receptors
IFNARI
IFNAR2c
IFNAR2b
IFNR
IFNR
type I IFN receptor type II IFN receptor
cell membrane
type I IFN: IFN and IFN, type II: IFN
chemokine receptor family: CCR1-5, CXCR1-4
NH3
COOH
binding of a ligandto the receptor
Cytokine Receptors
cell membrane
chemokine receptor family: CCR1-5, CXCR1-4G-Protein-Coupled Receptor (GPCR)
Cytokine Signalingcytokines
membrane receptors
phosphorylation cascades
gene transcription, Ca++ influx…
signal transduction
binding
activation
Cytokine Signaling
NFB signaling pathways
JAK/STAT signaling pathways
Chemokine/GPCR signaling pathways
Cross-talk between pathways
NFB Signaling
NFB signaling inducers: cytokines: IL-1, TNF,… microbial cell components: Fn cell wall, lipopolysacchrides (LPS),… virus: retroviruses, double-stranded RNA (dsRNA),…
Receptors: IL-1 receptors Toll-like receptors (TLRs, innate immunity) TNF receptors
Nuclear Factor B (NFB): dimeric transcription factors: p65/RelA, c-Rel, RelB, p105/p50, p100/p52 sequestered by inhibitory IB proteins and retained in cytosol in resting cells
NFB
IRAK
TRAF6pp
IRAK
4
pellino1
IB
IBp
p
TF
IRAK pp
p
p
u
u
degradation
u
TAK1
TAK1
activ
atio
n
uu u
u
pp IBIB
ubiquitination°radation
uu TRAF6
pTAK1
TAB1
TAB3
TAB2Ubc13/Uev1A
complex III
IRAK
TRAF6pp
IRA
K4
pe
llin
o1
TAK1
TAB1
TAB3TAB2
p
complex II
NEMO
IKKIKK
pIK
Kac
tivat
ion
p
u ubiquitination
phosphorylation
IL-1 receptor
IRAK
Tollip MyD88
IRAK4
TRAF6pp
complex I
IL-1
nucleus
cell
mem
bran
e
TNFaIL-6IL-8hBD-2….
innate&adaptiveimmunity
p
NFB
activ
atio
n
NFB p
nucl
ear
trans
loca
tion
pTF NFB p
JAK/STAT Signaling Pathway
JAK (Janus Kinases): a family of tyrosine kinases, JAK1-3, Tyk2
STAT (Signal Transducers and Activators of Transcription): transcription factors, STAT1-6,…
Cytokines: IFN/, IFN-, Epo, GM-CSF, IL-6, IL-13…
in resting cells, non-phosphorylated, monomeric STATs reside in cytoplasm.
SJ Baker et al, Oncogene (2007) 26, 6724–6737.
cdc25a, cyclin D1~3,c-myc, cyclin E, MMP9p21, caspase 3, 1, 8…
Chemokine Signaling
2 major families: the CCL (C-C motif ligand) family and CXCL (C-x-C motif ligand) family
CCL1~27, CXCL1~14
receptors: G-protein coupled 7 transmembrane receptor (GPCR)
Gi
SDF
PI-3K MAPK PLC
target genes
Adhesion, polarization, chemotaxis
CCL12 (SDF) signaling
p
p GRK-arrestin
recyclingdegradation
SDF
pathogens/infectionbacteria, virus
inflammationchemokine production, recruitment of phagocytes….
increased blood supply, capillary permeability, leukocyte migration
killing of pathogensneutralizing toxins, limiting pathogen spread
tissue repairphagocytosis of debris, pathogens, dead cells; cells growth
resolutionelimination of a pathogen, disappearance of leukocytes, full
regeneration of tissue function
Failure of acute inflammation resolution leads to chronic inflammation and autoimmune disorders
Examples: periodontal diseases (PD)chronic inflammation after dental treatment
Cytokines and Periodontal Diseases (PD)
the most common diseases in the world and the leading cause of tooth loss, a chronic infection that slowly attacks and destroys the gums and bone that support the teeth.
• caused by bacterial (~200 species) infection
• followed by a persistent immune response
• resulted in tissue damage
bacteriaA. actinomycetemcomitans, P. gingivalis, B. forsythus, T.
denticola, T. socranskii, P. intermedia
cell wall components(lipopolysaccharides, LPS)
exotoxins hydrolytic enzymes
inhibit antimicrobial peptides (lysozymes) activity
toxic to phagocytes (macrophages)
tissue damage/bone resorption
stimulate cytokine production of immune cells/chronic inflammation
Bacteria
LPS, exotoxin, etc.
binding to Toll-like receptors (TLRs)
activation of the NFkB signaling pathway in immune cells and epithelial cells
TNF, IL-1, IL-6, IL-8, IFN/, chemokines…perodontitis(autoimmune disorder)
neutrophilsmacrophages
dendritic cells(DCs)
T cellsB cells
phagocytosisH2O2, NOAMP
Tumor Necrosis Factor (TNF) produced by activated macrophages and T cells most important mediator of acute inflammation in response to microbes, such as LPS produced by the LPS-membrane bound Toll-like receptors
(TLRs) mediates recruitment of neutrophils and microphages to site of inflammation stimulates endothelial cells and macrophages to produce chemokines a potent pyrogen causing fever by direct action or via IL-1 promotes production of acute phase proteins, such as CRP roles in rheumatoid arthritis, psoriasis, tuberculosis, …
TNF and PD
• high in diseased periodontal tissues
• influences leukocyte migration
• corrected with RANKL and matrix metalloproteinase (MM) production
• stimulates IL-1, IL-8, IL-6 proinflammatory cytokine production
central role in inflammatory reaction, alveolar bone resorption, and the loss of connective tissue attachment
Interleukin 1 (IL-1)
Produced by activated macrophages, stimulated lymphocytes, keratinocytes, fibroblasts Activates the NFB signaling pathway (similar effects to TNF) Helps activate T cells Can be induced by inflammation, injury, and infection
Summary (PD and cytokines)
TNF and IL-1 play critical roles in amplifying the inflammatory response, leading to production of lytic enzymes and proinflammatory cytokines in PDs.
TNF and IL-1 antagonists block the progression of the inflammatory cell infiltrate and prevent the periodontal lesions
Cytokinesproperties, categories, signaling, function
What are cytokine?Interleukines, chemokines, monokines, …cytokine receptorsNFkB, JAK/STATA, chemokine signaling pathwaysrole of cytokines in immunomodulationcytokines and oral diseases (PD)
Recommended