Cytokines in allergic inflammation

Cytokines in allergic

inflammation

Reviewed by Sirapassorn Sornphiphatphong, MD.

Overview

• Classes of Cytokine receptors

• Allergic Immunity

• Antiinflammatory Cytokines

• T Helper Lymphocyte Families

• Cytokines Involved in Th1 Differentiation

• Cytokines Involved in Th2 Differentiation

Cytokines

• Secreted proteins of immune system

• Growth, differentiation and activation functions that

regulate immune responses

• Produced by many different cell types

• Others called interleukins

• All cytokine receptors consist of one or more

transmembrane proteins

– Extracellular portions: for cytokine binding

– Cytoplasmic portions: initiation of intracellular

signaling pathways

Middleton 8th edition

Classes of Cytokine receptors

based on extracellular cytokine-binding domains

• Type I Cytokine Receptors (Hematopoietin Receptor

Family)

• Type II Cytokine Receptors (IFN Receptor Family)

• TNF Receptor Family

• IL-1/TLR Family

Abbas AK, et al. Cellular and molecular immunology Ed 8th

Classes of Cytokine receptors


Type I Cytokine Receptors

(Hematopoietin Receptor Family)

• Dimers or trimers

• Contain 1 or 2 domains with

a conserved cysteines

• Proximal peptide stretch

containing a tryptophan-

serine-X-tryptophan-serine

(WSXWS) motif (X = amino

acid)


Subunit composition of cytokine receptors


Subunit composition of cytokine receptors

• Divided into subgroups based on structural

homologies or use of shared signaling polypeptides

• Common γ chain (CD132)

– Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, IL-21

• Common β chain (CD131) subunit

– Receptors for IL-3, IL-5, GM-CSF

• Common gp130 signaling component

– For IL-6, IL-11, IL-27, LIF, CNTF

Type II Cytokine Receptors

(IFN Receptor Family)

• 2 extracellular

domains with

conserved cysteines

• Do not contain

WSXWS motif

• Signaling through

type I, type II cytokine

receptor: JAK-STAT

signaling


TNF Receptor Family

• Preformed trimers

• Conserved cysteine-rich

extracellular domains

• Shared intracellular signaling

mechanisms

• TNFRI & TNFRII, CD40

protein, Fas, lymphotoxin

receptor & BAFF receptor

family


TNF Receptor Family


TNF Receptor Family

• Binding ligands to trimeric receptors conformational

change & recruits adaptor proteins to receptor complex

• Adaptors recruit enzymes which initiate downstream

signaling

• TNF receptor recruits adaptor protein TRADD (TNF

receptor–associated death domain)

• TRADD can recruit proteins called TRAFs (TNF receptor

associated factors) on NF-κB signaling

• Type I TNF receptor (there are 2 R for TNF) & Fas

(CD95) can also recruit adaptors activation of

caspase-8 apoptosis

IL-1/TLR Family

• Share a conserved cytosolic

sequence, called Toll-like/IL-1

receptor (TIR) domain engage

similar signal transduction

pathways induce new gene

transcription

• Adaptors link TLRs to different

IRAK (IL-1R–associated kinase)


Allergic Immunity

• Proinflammatory T cell activation → development

of allergic immunity

• Several features specifically associated with the

asthmatic state are regulated by cytokines,

including IgE production, eosinophil activation,

and mast cell proliferation

Cytokine in allergic immunity

• Regulation of IgE – Induction of IgE: IL-4, IL-13, IL-9

– Inhibition of IgE Production: IFN-γ, IL-21

• Eosinophilia – IL-5, IL-3, GM-CSF

• Mast cell proliferation and activation

• Other Th2 derived cytokines involved in the development of allergic inflammation – IL-31

Regulation of IgE

• Inappropriate production of IgE in response to

allergen defines atopy

• Induction of IgE

• Primarily a function of IL-4, IL-13

• Synergistic by IL-9

• Inhibitors of IgE isotype switch: IFN-ɣ, IL-21

IL-4 and IL-13


IL-4 and IL-13 • Shared use of IL-4Rα chain by IL-4 & IL-13

• Shares many biologic activities on mononuclear

phagocytic cells, endothelial cells, epithelial cell, B cells

• Activation signaling protein STAT6

• Induces IgE isotype switch, VCAM-1 expression


IL-4 • The limited distribution of IL-13Rα1 explains unique

ability of IL-4 to induce Th2 lymphocyte

differentiation and mast cell activation


IL-4

• Enhancing Ag-presenting capacity

- Stimulates MHC-II, B7 (CD80/CD86), CD40, surface

IgM, and low-affinity IgE R(CD23) on macrophages

• Downregulate antibody-dependent cellular

cytotoxicity

• Inhibit expression of Fcγ receptors

• IL-4 receptors present on mast cells

- Stimulate IgE receptor expression

- Expression of LTC4 synthase produce cyst LT

IL-13

• More in allergic inflammatory tissue

• Stimulate mucin production in asthma (more

than IL-4)

• Mucous hypersecretion, nonspecific airway

hyperreactivity (AHR)

• Airway metaplasia of asthma

IL-9

• Produced by Th9, Th2, mast cell, eosinophil

• Mast cell growth factor

• Synergizes with IL-4 to enhance production of

IgE, memory B cell differentiation

• Enhanced IL-5

• Induce T cell & eosinophil chemotactic factors

• Important role in inducing goblet cell hyperplasia

& expression of mucin genes

Eosinophilia

• IL-5

• IL-3

• GM-CSF

Tetsuya Adachi , Rafeul Alam Cell Physiology 1998;275:C623-C633

IL-5Rα and β chain(CD131) shared

with GM-CSF, IL-3 receptors

IL-5 IL-3 GM-CSF Th2-like lymphocytes,

mast cells, NK T cells

T lymphocytes (major source)

Eosinophils, mast cells (in allergic inflammation)

Eosinophil •Stimulating production •Chemotactic and activates mature eosinophils •Inducing secretion and enhancing cytotoxicity •Promotes accumulation of eosinophils

•upregulate responses to chemokines, β2 integrins on eosinophils •promote adherence to VCAM-1 expressing endothelial cells

•Prolongs eosinophil survival by blocking apoptosis

Induce basophil

differentiation

supports growth: DCs,

erythrocytes, granulocytes

(especially basophils),

macrophages, mast cells,

and lymphoid cells

supports the maturation of

DCs, neutrophils, and

macrophages

Mast cell proliferation and activation

• Cytokine for mast cell growth, proliferation

– Stem cell factor (SCF) (formerly termed c-kit ligand)

– IL-3, IL-5, IL-6, IL-9, IL-10, IL-11, nerve growth factor

Stem cell factor (SCF)

• Derived from bone marrow stromal cells, endothelial

cells, fibroblasts

• Induces histamine release

• Stimulate myeloid, lymphoid, and erythroid progenitor

cell growth and mast cell differentiation

IL-31

• IL-6–type cytokine family

• Expressed by Th2-like lymphocytes

• Targets keratinocytes, epithelial cells,

eosinophils, basophils and monocytes

• Recruitment of neutrophils, monocytes, and T

cells

• Overexpression: AD

Antiinflammatory Cytokines

• TGF-β

• IL-10 family: IL-10, IL-19, IL-20, IL-22,

IL-24, IL-26, IL-28, and IL-29

Transforming growth factor-β

• Regulate cell growth, both stimulatory and

inhibitory effects on different cell types

• Produced by osteocytes, epithelial cells,

fibroblasts, platelets, monocytes, eosinophils,

and T cells

• Stimulant of fibrosis, formation of ECM and the

promotion of wound healing and scar formation

TGF-β

• Inhibits Ig secretion and cytotoxicity of mononuclear phagocytes and NK cells

• Chemoattractant for macrophages

• Supports the α isotype switch to IgA

TGF-β in gut lymphoid tissue by Th3 cells

• secretory IgA production

• immune nonresponsiveness to benign gut pathogens and food allergens

TGF-β production by regulatory cells

• lessens allergic inflammation through a capacity to inhibit IgE synthesis and mast cell proliferation

IL-10

• Source

– Treg: primary source

– Th1, Th2 lymphocytes, cytotoxic T cells

– B lymphocytes

– mast cells

– Immature DCs, mononuclear phagocytic cells (M2 cells)

• Signaling through activation of JAK1-STAT3

Function

• Inhibit cytokine:

– Th1 cytokine (IFN-γ)

– Th2 cytokine(IL4, IL5)

– mononuclear phagocytes cytokine (IL-1β, IL-6, IL-8, IL-12, and TNF-α)

– NK cells cytokine (IFN-γ and TNF-α)

• Inhibits MHC class II, CD23, ICAM-1 and CD80/CD86

• Enhances isotype switching to IgG4

• Growth cofactor for cytotoxic T cells

IL-10 family

• IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29

• Share structural homology with IL-10 and IL-10 receptors

• Antiviral activity

• None of these cytokines inhibit cytokine synthesis, an activity that remains unique to IL-10

IL-10 family

IL Source Pathway Function

IL-19 Monocytes, epithelial,

endothelial cells

STAT1,

STAT3 Promote Th2, asthma

IL-20 Monocytes, DCs,

epithelial cells,

endothelial cells,

skin keratinocytes

STAT1,

STAT3

keratinocyte proliferation,

psoriatic lesions

IL-22 Th17 and Th1 cells),

NK cells

STAT3 Innate pathogen defense, induces

MHC class I antigen expression

Il-24 Monocytes, Th2 STAT3 Promotes secretion of TNF-α , IL-

6 from human monocytes,

antineoplastic activity

IL-26 T memory cells, Th17

cells, and NK cells

STAT1, STAT3

Induce CXCL8 (IL-8), ICAM-1

IL-28A,

IL-28B

JAK/STAT Antiviral, Shift immature DCs to

produce Treg

T Helper Lymphocyte Families

• Th1

• Th2

• Th17-like lymphocytes

• Other T Helper Families: Th9, Th22, T Follicular

Helper Cells

• Regulatory T lymphocytes families: Treg, TR1,

AND Th3 CELLS



Cytokines Involved in Th1 Deviation


Cytokines Involved in Th2 Deviation


Epithelium-derived cytokines in

Th2 differentiation

IL 25: increase expression of CCL5 (RANTES), CCL11(eotaxin)

IL33: express in bronchial epithelial cell induces fibrosis Middleton 8th edition

Th17 Differentiation


Th9 lymphocytes


• Subfamily of Th2 cells

• Prominent IL-9, moderate IL-10, less IL-4

• Result from the differentiation of Th2

cells in the presence of TGF-β

Th22 lymphocytes

• Prominent expression of IL-22, TNF-α

• Produced by keratinocytes or epithelial cells

• ↑IL-22 correlated with severity disease of

Psoriasis, Crohn disease, interstitial lung

diseases and rheumatoid arthritis


TGF -B

T follicular helper cell (Tfh)

• Defined by their follicular location

• Interacts with B cells in the germinal center

– Support affinity maturation

– Isotype switching

– Produce memory B and long-lived plasma cells

• BCL6: master regulator

– Increases expression of CXCR5, PD-1 -> express IL-21


Treg


TREG, TR1, AND Th3 CELLS

• Thymus-derived natural

regulatory T cells (nTreg)

cells

– Response to thymus-

autologous Ag mediate

tolerance to self Ag

– Secrete membrane-

bound TGF-β

• Inducible Treg (iTreg) cells

– Secrete IL-10

– Response to peripherally

expressed self Ag

• Unique expression profiles

and functions

• TGF-β–producing Th3 cells

of the gut mucosa

– Mediate IgA production

• IL-10–producing

lymphocytes; Tr1

– Mechanism of IT



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Cytokines in allergic inflammation