cytokines and signaling pathways in healthy and disease dent516 ge jin, ph.d. email: [email protected]...
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Cytokines and signaling pathways inhealthy and disease
DENT516
Ge Jin, Ph.D.Email: [email protected]: 3683791Office: DO3570, School of Dental Medicine
March 26, 2012
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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
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Immune cells and the mediators they produce
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Cytokines
small, secreted, non-antibody proteins
produced by cells involved in both innate & adaptive immunity
mediate and regulate immunity, inflammation, and hematopoiesis
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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)….
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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)
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Properties of Cytokines
can be produced by many cell types and act on many cell types (pleiotropic)
different cytokines can have similar actions (redundant)
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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
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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
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TNFR family: TNF, FasL, CD40L…
Cytokine Receptors
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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
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-- 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)
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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
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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)
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Cytokine Signalingcytokines
membrane receptors
phosphorylation cascades
gene transcription, Ca++ influx…
signal transduction
binding
activation
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Cytokine Signaling
NFB signaling pathways
JAK/STAT signaling pathways
Chemokine/GPCR signaling pathways
Cross-talk between pathways
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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
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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
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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.
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SJ Baker et al, Oncogene (2007) 26, 6724–6737.
cdc25a, cyclin D1~3,c-myc, cyclin E, MMP9p21, caspase 3, 1, 8…
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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)
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Gi
SDF
PI-3K MAPK PLC
target genes
Adhesion, polarization, chemotaxis
CCL12 (SDF) signaling
p
p GRK-arrestin
recyclingdegradation
SDF
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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
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Failure of acute inflammation resolution leads to chronic inflammation and autoimmune disorders
Examples: periodontal diseases (PD)chronic inflammation after dental treatment
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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
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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
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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
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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, …
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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
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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
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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
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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)