CYTOKINES

Cytokines are important because:

• Master regulators of the immune system

• Therapeutic reagents

Cytokine Nomenclature• Monokines - cytokines produced by moncytes• Lymphokines - cytokines produced by activated T

cells• Interleukins - cytokines produced by leukocytes

which act leukocytes• Interferons - cytokines important in controlling viral

infections and augmenting immune responses• Colony-Stimulating Factors - cytokines important in

the maturation of leukocytes• Chemokines - cytokines important in directed

migration of leukocytes during immune responses• Growth Factors - cytokines involved in stem cell

differentiation and other functions

Cytokine Functions Are:

• PLEIOTROPIC

• REDUNDANT

• SYNERGISTIC

• ANTAGONISTIC

CYTOKINE PROPERTIES

• Low molecular weight proteins or glycoproteins

• Synthesized in active and inactive forms• Secretion is brief and self-limiting• Active at very low concentrations• Signal cells by binding to specific

receptors on target cells

Cytokine Receptors

• Each cytokine has a receptor• Receptors are grouped into 5 families• Cytokine receptors are often multi-

chain complexes• Signaling through receptors requires

multiple events

IL-1IL-2

IL-8 and chemokines

IFN-a, b, g TNF-a, b

Cytokine Receptor Subfamilies

Signaling receptorsubunit

Cognate receptorsubunit

Generalized Cytokine Signaling Mechanism

a -ChainCognate receptor

b-ChainSignaling receptor

JAKPP

PP P

P

Transcription

P PSTATs

Nuclear membrane

Cytokine Effects on Target Cells are:

•AUTOCRINE -

•PARACRINE -

•ENDOCRINE -

Hematopoietic Cytokines in the Immune System

Cytokines are critical for lymphocyte development

T Cell Maturation and Cytokines

• Dependent on IL-2 for activation, growth and proliferation after Ag binding

• Differentiation to helper T cell subsets (Th1 and Th2) depends on cytokines

• Th1 cells produce cytokines that aid cell-mediated immunity (IFN-g, IL-2 , others)

• Th2 cells produce cytokines that aid antibody production (IL-4, IL-5, others)

• Dependent on multiple cytokines for activation, growth and proliferation after Ag binding

• IL-6 is a major growth factor for B cells• Multiple cytokines are involved in isotype

switching (e.g., TGF-b for IgA, IL-4 for IgE)

B Cell Maturation and Cytokines

Cytokines in Host DefenseViral Infections

• Viruses infect by binding to a “receptor” and are internalized

• Take-over host machinery, replicate DNA or RNA

• Viral genetic material is recognized as foreign by TLRs (TLR3 - dsRNA, TLR8 - ssRNA)

• Viral TLR binding leads to production of “Interferons” - anti-viral cytokines critical to clearing viral infections

Viral Responsive TLRs

ssRNA

INTERFERONS

Two Major Interferons:Types I and II

Type I: produced by all cells (IFN-a/b)

Type II: produced by act. T cells (IFN-g)Functions:• innate immunity - viral clearance• adaptive immunity - lymphocyte

activation/maturation

Interferon anti-viral mechanisms

• Induce the expression of MHC molecules

• Shut down infected host cells

- Allows Ag presentation to cytotoxic T cells- Loss of MHC expression allows targeting by NK cells

- production of 2-5 (A) synthase -> activates RNAse L -> degrades mRNA- PKR inactivates eIF-2 (a translation factor) -> blocks protein synthesis

Cytokines in Host DefenseBacterial Infections

• Bacteria infect by a number of routes - ingested, inhaled, through cuts

• Take over a niche and replicate rapidly

• Bacterial PAMPS are recognized as foreign by TLRs (TLR4 - LPS, TLR5 - flagellin)

• Bacterial PAMP binding to TLRs leads to production of pro-inflammatory cytokines and the acute phase response, critical to clearing bacterial infections

Bacterial PAMP Responsive TLRs

ACUTE PHASE RESPONSE

A well orchestrated sequence of events to mobilize a metabolic response of the organism to:

• Eliminate invading pathogens• Prevent on-going tissue damage• Activate repair processes

Mediated by “pro-inflammatory” cytokines including TNF-a, IL-1, IL-6, IL-8 and IFN-g

Tumor Necrosis Factor-a (TNF-a)Interleukin 6 (IL-6)Interleukin 1 (IL-1)

• Production induced by LPS and other PAMPS, made by MØ, fibroblasts, others

• Activates myeloid cells, epithelium, endothelium• Induce production of multiple cytokines• Initiates acute phase response (fever)• Induces adhesion molecule expression• Toxic at high levels (septicemia)

Acute Phase Proteins

• Host Defense Proteins

• Proteinase Inhibitors

• Anti-oxidants

CRP, complement, fibrinogen

C1 inhibitor, a1-proteinase inhibitor

Haptoglobin, ceruloplasmin

Chemokines• Multiple families of small molecular weight

cytokines (at least 60 at present time)• Classified based on different cysteine motifs• Involved in multiple immune functions

including inflammation, cell recruitment, lymphocyte trafficking, lymphoid organ development and wound healing

• Expressed in primary and secondary lymphoid organs

Clinical Applications of Cytokines

•Some of your patients will be receiving cytokine therapy for non-dental/optometry conditions

•Cytokine-specific therapies are in use for some dental/optometry conditions

Cytokine Therapy

• Interferon-a therapy for chronic myeloid leukemia - disease remission

• Soluble TNF-a receptor (Infliximab) - therapy for rheumatoid arthritis

• Interferon-b therapy for multiple sclerosis - effective in about 30% of patients

• Procrit (erythropoietin) to boost RBC levels in patients undergoing chemotherapy

Cytokine Therapy for the Eye

• Anti-TNF-a antibody in refractory posterior uveitis - restored visual acuity

• Nerve growth factor heals corneal ulcers refractory to conventional therapy - no side effects

• Interferon-a treatment of Bechet’s disease reduces retinal inflammation, improves visual acuity

Cytokine Therapy for the Oral Cavity

• Thalidomide (anti-TNF-a) therapy for orofacial granulomatosis - clinical resolution

• Soluble TNF-a receptor therapy prevents root resorption in a rat model system

• Interferon-a therapy combined with surgery clinically resolves aggressive oral giant cell tumors