Post on 22-Dec-2015
Lecturer: Ge Jin, Ph.D., ge.jin@case.edu, 3683791
Learning Objectives:
1. describe basic properties of cytokines
2. describe how cytokines regulate immunity (e.g. increase or decrease MHC expression and T cell activation…)
3. cytokine and oral diseases
NOTE: you need to download the PowerPoint file to your computer to read notes.
Slides containing research results from my lab will be added during the lecture.
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)….
Cytokines
grouped by structures into families
interferons (IFN): type I (IFN and IFN), type II (IFN)
Interleukin: IL-1, IL-2
chemokine: CXCL and CCL chemokines
TNF: TNF, FasL, CD40L…
hematopoietin: erythropoietin (EPO), colony- stimulation factors (CSF)
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)
-- 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)
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
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
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
Cytokine Receptors
TGF receptors
TGF receptors have intrinsic kinase activity when interacting with ligands.
Cytokine Signalingcytokines
membrane receptors
phosphorylation cascades
transcription, Ca++…
signal transduction
binding
activation
Cytokine Signaling
NFB signaling pathways
JAK/STAT signaling pathways
Chemokine 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
IL-6IL-8hBD-2….
innate&adaptiveimmunity
p
NFB
activ
atio
n
NFB p
nucl
ear
trans
loca
tion
pTF NFB p
NFB Signaling
Alternative NFB activation pathways of immunity
CD40L, LT-B, BAFF
NIK
IB degradation
NFB activation
CD4/TCR
PKC
UV-light
p38-CKII
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 cytosol
IFN/IFN
receptorbind
ing
phos
pho-
ReceptorJAKs
ReceptorJAKsSTATs
DNA STATdimers
target genetranscription
phos
pho-
trans
loca
tion
nucleusbi
ndin
gcdc25a, cyclin D1~3,c-myc, cyclin E, MMP9p21, caspase 3, 1, 8…
Chemokine Signaling
2 major families: the CCL family and CXCL family
CCL1~27, CXCL1~14
receptors: G-protein coupled 7 transmembrane
Gi
SDF
PI-3K MAPK PLC
target genes
Adhesion, polarization, chemotaxis
CCL12 (SDF) signaling
p
p GRK-arrestin
recyclingdegradation
SDF
Cross-talk between CytokineSignaling Pathways
chemokinereceptor
interferonreceptor
IL, TLR, TNFreceptors
STATs NFB
PI-3K
TAK1
TGFreceptor
Cytokines and Immunoregulation
Mediators of Innate Immunity
Mediators of adaptive immunity
Stimulators of hematpoiesis
Cytokines and Immunoregulation
Mediators of Innate Immunity
TNF IL-1 IL-10 IL-12 IFN, IFN IFN Chemokines
Mediators of adaptive immunity
Stimulators of hematpoiesis
Tumor Necrosis Factor (TNF) Produced by activated macrophages and T cells Most important mediator of acute inflammation in response to microbes, such as LPS Induces production of myeloid CSFs, IFN-, IL-6, IL-8 and other chemokines Mediate recruitment of neutrophils and microphages to site of inflammation by stimulating cells to produce adhesion molecules (e.g. ICAM-1) 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, …
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
Interleukin 10 (IL-10)
Produced by macrophages, B cells, Th2 cells
Originally identified as cytokine synthesis inhibitory factor
Suppresses inflammatory responses
Inhibits production of IFN-, IL-2, IL-3, TNF, GM-CSF
Stimulate thymocytes, mast cells, B cells
Limits Th1 response, promotes Th2 cell development, shifts response to Th2 type (phagocytosisAb production)
Inhibits expression of class II MHC and co-stimulatory molecules on macrophages
Interleukin 12 (IL-12)
Produced by macrophages, dendritic cells, Tc cells, NK cells Belongs to the IL-6 cytokine family Has immunoregulatory effect on NK cells and T cells Stimulates production of IFN- Promotes Th cells Th1 Enhances differentiation of Cytotoxic T Lymphocytes (with IL-2) Enhances cytolytic functions of T cells and NK cells
Type I Interferon (IFN-, IFN-)
Produced by macrophages and virus-infected cells
Inhibits viral replication in cells via PKR and RNaseL
Increases expression of MHC I and Tc mobilization
Stimulates production of IFN- by activated T cells
Activate NK cells
Type II Interferon (IFN-)
Produced primarily by Th1
Induce ICAM production in endothelial cells
Activate NK cells
Increase MHC I and MHC II expression to help Th cell and
APC interaction
Promotes B cell differentiation to plasma cell
Promotes cytotoxic T cell differentiation
Chemokines
Produced by many leukocytes and other types of cells
Large family of molecules (over 50)
Have significant structural homology and overlapping functions
Chemotactic for leukocytes, such as PMN, T and B cells
Recruit leukocytes to sites of infection and inflammation
Involved in lymphocytes trafficking, wound healing, metastasis, angiogenesis, lymphoid organ development….
Cytokine in ImmunregulationMediators of Innate Immunity
Mediators of adaptive immunity IL-2 IL-4 IL-5 TGF IL-10 IL-12 IFN-Stimulators of hemotopoesis
Interleukin 2 (IL-2) Produced by lectin- or antigen-activated Th cells Powerfully immunoregulatory lymphokine Main growth factor for both T and B lymphocytes Activates NK cells and monocytes
CTLA-4: Cytotoxic T-Lymphocyte Antigen 4, inhibits T cell function.
Interleukin 4 (IL-4)
Produced by macrophages, Th2 cells, activated B cells Has complex biological actions via cytokine production Enhances antigen-presenting activity of B to T cells Stimulates development of Th2 cells from naïve Th cell Stimulates Ig class switch from IgG1 to IgE (allergy)
Interleukin 5 (IL-5)
Produced by Th2 cells Originally identified as a B cell differentiation factor Aids in the growth and differentiation of eosinophils and
late-developing B cells to plasma cells
Transforming growth factor (TGF)
Produced by T cells, macrophages, other cell types
30 members
Have effect on many cell types
Have pro- and anti-inflammatory effect
Inhibits proliferation of T cells and activation of B cells
Acts on PMNs and endothelial cells to block the effects of pro-inflammatory cytokines
Cytokine and Immunoregulation
Mediators of Innate Immunity
Mediators of adaptive immunity
Stimulators of hematopoiesis (Colony Stimulating Factors)
GM-CSF: promotes differentiation of bone marrow progenitors
M-CSF: promotes growth and differentiation of monocytes and macrophages
G-CSF: promotes production of PMNs
Regulation of Immune Responsesregulatory mechanisms: antibody
antibody competes with B cellsfor antigen
antigen/antibody complexesbinding to Fc receptors sendsan inhibitory signal to B cells
Regulation of Immune Responsesregulatory mechanisms: Tregs
Regulatory T cells (Tregs) do not inhibit initial T cell activation and proliferation They are not Th1 or Th2 cells They can suppress both Th1 and Th2 responses They inhibit a sustained response and prevent chronic and potentially damaging responses
Regulation of Immune Responsesregulatory mechanisms: Tregs
Naturally occurring Tregs
CD4+CD25+Foxp3+ cells derived from thymus
IL-2, cell contact dependent inhibition
Foxp3 is required for Treg development
Foxp3
CD25 (part of IL-2R)CD4
Regulation of Immune Responsesregulatory mechanisms: Tregs
Induced Tregs
CD4+CD25+Foxp3+ cells induced by antigen
CD25 (part of IL-2R)CD4 CD4
T cells
antige+IL-10
TGFFoxp3
Treg cells
Cytokines and Oral Diseasesbacterial colonization
periodontal disease (PD)
bacterial invasion
osteoclast formation/bone loss
host responses
chemokines: bone resorption, osteoclast survival
IL-1: up-regulated, stimulates bone loss
IL-6: proinflammatory to bone resorption
TNF: induces cytokine production, stimulate inflammation and bone loss
RNAKL: inducer of osteoclast formation and activity, bone loss
Colony stimulating factors (CSFs) hematological disorders associated with cancer therapy
Erythropoietin (EPO) anemia associated with kidney disease
IFN- multiple sclerosis
IFN- chronic granulomatous disease (GCD)
IL-2 kidney cancer, melanoma
IL-11 thrombocytopenia following high dose chemotherapy
TNF mAb Infliximab for rheumatoid arthritis and Crohn’s disease
Cytokines and Clinical Applications