Download Cytokines

Lecturer: Ge Jin, Ph.D., [email protected], 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.
Body as Host: Immune Molecules
Cytokines
properties, categories, signaling, function
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 a (TNFa),
Colony Stimulation Factor (CSF), Transforming Growth Factor b
(TGFb)….
Cytokines
 grouped by structures into families
 interferons (IFN): type I (IFNa and IFNb), type
II (IFNg)
 Interleukin: IL-1, IL-2
 chemokine: CXCL and CCL chemokines
 TNFa: TNFa, FasL, CD40L…
 hematopoietin: erythropoietin (EPO), colonystimulation 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-2Rg defect Xlinked SCID (Severe Combined Immunodeficiency)
Properties of Cytokines
 can modulate synthesis of other cytokines
- cascades: e.g. TNFa 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
Cytokine Receptors
(grouped by structures into families)
Immunoglobulin superfamily: IL1R, TLRs…
leucine-rich
repeats
immunoglobulin
domain
cell membrane
Toll-IL-1 Receptor
domain (TIR)
IL-1 receptor
Toll-like
receptors (TLRs)
Cytokine Receptors
TNFR family: TNFa, FasL, CD40L…
Cytokine Receptors
class I receptor family: hematopoietin family
CNTF LIF/OSM
IL-6
GM-CSF IL-3
IL-5
b
IL-2b
g
IL-9R
IL-7 IL-9
IL-7R
IL-15Ra
IL-2Ra
IL-5R
IL-3R
b
g
IL-15
g
g
IL-2b
cell membrane
GM-CSF: Granulocyte macrophage colony-stimulating factor
IL: interleukin
gp130: glycoprotein 130 (m.w. 130 kDa)
CNTFR
GM-CSFRa
IL-2
b
IL-11
gp130 gp130 gp130 gp130
cell membrane
Cytokine Receptors
class II receptor family: Interferon a, b, and g
IFNARI
IFNgRb
IFNAR2b
IFNAR2c
cell membrane
type I IFN receptor
type I IFN: IFNa and IFNb, type II: IFNg
IFNgRa
type II IFN receptor
Cytokine Receptors
chemokine receptor family: CCR1-5, CXCR1-4
NH3
cell membrane
binding of a ligand
to the receptor
Cytokine Receptors
TGFb receptors
TGFb receptors have intrinsic kinase activity when interacting with ligands.
Cytokine Signaling
cytokines
binding
membrane receptors
signal transduction
phosphorylation cascades
activation
transcription, Ca++…
Cytokine Signaling
 NFkB signaling pathways
 JAK/STAT signaling pathways
 Chemokine signaling pathways
 Cross-talk between pathways
NFkB Signaling
Nuclear Factor k B (NFkB):
 dimeric transcription factors: p65/RelA, c-Rel, RelB, p105/p50,
p100/p52
 sequestered by inhibitory IkB proteins and retained in
cytosol in resting cells
NFkB signaling inducers:
 cytokines: IL-1, TNFa,…
 microbial cell components: Fn cell wall, lipopolysacchrides (LPS),…
 virus: retroviruses, double-stranded RNA (dsRNA),…
Receptors:
 IL-1 receptors
 Toll-like receptors (TLRs, innate immunity)
 TNFa receptors
IL-1
p
IRAK4
pellino1
pellino1
Tollip MyD88
p
IRAK p
p
IRAK p
IRAK4
TRAF6
TRAF6
complex I
IL-1 receptor
p
u
IRAK p
TAB1
TRAF6
TAB2
TAK1 TAB3
p
p
IRAK p
p
u
u
complex II
degradation
p
IkB
NFkB
p
p
IkB
u
u
IkB
u Ubc13/Uev1A
u TRAF6 TAB2
TAK1 TAB3
p
TAB1
p
IKKb
IKKa
TAK1
complex III
IkB
u
u
nucleus
p
p
NFkB p
ubiquitination&
degradation
TF NFkB
p
p
TF
phosphorylation
u ubiquitination
p
IL-6
IL-8
hBD-2
….
innate
&
adaptive
immunity
NFkB Signaling
Alternative NFkB activation pathways of immunity
CD40L, LT-B, BAFF
CD4/TCR
UV-light
NIK
PKC
p38-CKII
IkB degradation
NFkB activation
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: IFNa/b, IFN-g, Epo, GM-CSF, IL-6, IL-13…
 in resting cells, non-phosphorylated, monomeric STATs
reside in cytosol
SJ Baker et al, Oncogene (2007) 26, 6724–6737.
IFNa/b
IFNg
receptor
target gene
transcription
cdc25a, cyclin D1~3,
c-myc, cyclin E, MMP9
p21, caspase 3, 1, 8…
DNA
Receptor
JAKs
Receptor
JAKs
STATs
nucleus
STAT
dimers
Chemokine Signaling
 2 major families: the CCL family and CXCL family
 CCL1~27, CXCL1~14
 receptors: G-protein coupled 7 transmembrane
CCL12 (SDF) signaling
Gai b
a
g
b
PI-3K
p
p GRK
a
b-arrestin
g
MAPK
PLC
recycling
degradation
target genes
Adhesion, polarization, chemotaxis
Cross-talk between Cytokine
Signaling Pathways
chemokine
receptor
interferon
receptor
IL, TLR, TNFa
receptors
TAK1
STATs
PI-3K
NFkB
TGFb
receptor
Cytokines and Immunoregulation
Mediators of Innate Immunity
Mediators of adaptive immunity
Stimulators of hematpoiesis
Cytokines and Immunoregulation
Mediators of Innate Immunity
 TNFa
 IL-1
 IL-10
 IL-12
 IFNa, IFNb
 IFNg
 Chemokines
Mediators of adaptive immunity
Stimulators of hematpoiesis
Tumor Necrosis Factor a (TNFa)
 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-g, 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, …
prothrombotic
macrophage
activation
hematopoiesis
lymphocyte
development
Interleukin 1 (IL-1)
 Produced by activated macrophages, stimulated lymphocytes,
keratinocytes, fibroblasts
 Activates the NFkB 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-g, IL-2, IL-3, TNFa, GM-CSF
 Stimulate thymocytes, mast cells, B cells
 Limits Th1 response, promotes Th2 cell development,
shifts response to Th2 type (phagocytosisAb 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-g
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-a, IFN-b)
 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-g by activated T cells
 Activate NK cells
Type II Interferon (IFN-g)
 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 Immunregulation
Mediators of Innate Immunity
Mediators of adaptive immunity
 IL-2
 IL-4
 IL-5
 TGFb
 IL-10
 IL-12
 IFN-g
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 b (TGFb)
 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
emdbiosciences.com
Regulation of Immune Responses
regulatory mechanisms: recognition phase
Regulation of Immune Responses
regulatory mechanisms: antibody
antibody competes with B cells
for antigen
antigen/antibody complexes
binding to Fc receptors sends
an inhibitory signal to B cells
Regulation of Immune Responses
regulatory 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 Responses
regulatory mechanisms: Tregs
Naturally occurring Tregs
CD4+CD25+Foxp3+ cells derived from thymus
IL-2, cell contact dependent inhibition
Foxp3 is required for Treg development
CD25 (part of IL-2R)
CD4
Foxp3
Regulation of Immune Responses
regulatory mechanisms: Tregs
Induced Tregs
CD4+CD25+Foxp3+ cells induced by antigen
antige+IL-10
CD4
CD4
CD25 (part of IL-2R)
TGFb
Foxp3
T cells
Treg cells
Cytokines and Oral Diseases
bacterial colonization
bacterial invasion
host responses
chemokines: bone resorption, osteoclast survival
IL-1: up-regulated, stimulates bone loss
IL-6: proinflammatory to bone resorption
TNFa: induces cytokine production, stimulate inflammation and bone loss
RNAKL: inducer of osteoclast formation and activity, bone loss
osteoclast formation/bone loss
periodontal disease (PD)
Cytokines and Clinical Applications
Colony stimulating factors (CSFs)
hematological disorders associated with cancer therapy
Erythropoietin (EPO)
anemia associated with kidney disease
IFN-b
multiple sclerosis
IFN-g
chronic granulomatous disease (GCD)
IL-2
kidney cancer, melanoma
IL-11
thrombocytopenia following high dose chemotherapy
TNFa mAb
Infliximab for rheumatoid arthritis and Crohn’s disease
Cytokines
properties, categories, signaling, function
What are cytokine?
Interleukines, chemokines, monokines, …
cytokine receptors
NFkB, JAK/STATA, chemokine signaling pathways
role of cytokines in immunomodulation
cytokines and oral diseases (PD)