Cytokines Non-antibody proteins acting as mediators between cells, termed: Monokines – mononuclear phagocytes Lymphokines – activated T cells, especially.

Cytokines

Non-antibody proteins acting as mediators between cells, termed:

• Monokines – mononuclear phagocytes• Lymphokines – activated T cells, especially

helper T cells• Interleukins – abbreviated IL with a number

Properties of Cytokines1. Produced by cells involved in both natural

and specific immunity

2. Mediate and regulate immune responses

3. Secretion brief and limited - not stored pre-formed - synthesis initiated by gene transcription - mRNA short-lived - cytokines produced as needed

Properties of Cytokines(continued)

4. Can be produced by many cell types and act on many cell types (pleiotropic)

5. Can have similar actions (redundant)

IL2

Rα

IL2

Rβ

IL2

Rγ

IL15

Rα

IL2

Rβ

IL2

Rγ

IL7

R

IL2

Rγ

?

IL9

R

IL2

Rγ

IL4

R

IL2

Rγ

IL-2 IL-15 IL-7 IL-9 IL-4Receptor for:

Properties of Cytokines (continued)

6. Can influence synthesis of other cytokines - produce cascades - enhance or suppress production of other

cytokines - exert positive or negative regulatory mechanisms

for immune responses7. Influence action of other cytokines - can be antagonistic, additive, synergistic

Properties of Cytokines (continued)

8. Bind to receptors with high affinity

9. Cells responding to cytokine can be:

- same cell (autocrine)

- nearby cell (paracrine)

- distant cell by circulation (endocrine)

10. Cellular responses to cytokines are slow, require new mRNA and protein synthesis

• Tumor Necrosis Factor-alpha (TNF-α)

• Interleukin-1 (IL-1)

• Chemokines (Chemotactic cytokines)

• Type I Interferons (IFN-α and IFN-β)

• Interleukin-12 (IL-12)

• Interleukin-10 (IL-10)

Mediators and Regulators of Natural Immunity

Tumor Necrosis Factor (TNF-α)

• Produced by activated macrophages• Most important mediator of acute inflammation in

response to microbes, especially Gram-negative bacteria (LPS)

• Mediates recruitment of neutrophils and macrophages to site of inflammation

• Acts on hypothalamus to produce fever• Promotes production of acute phase proteins

Interleukin-1 (IL-1)

• Produced by activated macrophages

• Effects similar to those of TNF-α

Chemokines

• Produced by many different leukocytes and tissue cells

• Large family of >50 substances

• Recruit leukocytes to sites of infection

• Play a role in lymphocyte trafficking

Type I Interferons (IFN-α and β)

• IFN-α a family of many proteins produced by macrophages, IFN-β a single protein produced by many cells

• Both IFNs inhibit viral replication• Both increase expression of class I MHC• Both activate NK cells

Interleukin-12 (IL-12)• Produced by activated macrophages and

dendritic cells

• Stimulates production of IFN-γ

• Induces differentiation of Th cells to become Th1 cells

• Enhances cytolytic functions of cytotoxic T cells and NK cells

Interleukin-10 (IL-10)• Produced by activated macrophages,

Th2 cells• An inhibitory cytokine• Inhibits cytokine production by

activated macrophages• Inhibits expression of class II MHC

and costimulatory molecules on macrophages

Mediators and Regulators of Specific Immunity

• Interleukin-2 (IL-2)

• Interleukin-4 (IL-4)

• Interleukin-5 (IL-5)

• Interleukin-10 (IL-10)

• Interferon-gamma (IFN-γ)

Interleukin-2 (IL-2)• Produced by Th>>Tc

• Main growth factor for T cells

IL-2secretion

T cell

NKIncrease in NK

Cell activity

B cell Stimulationof division

T cell

Stimulation of division and IFN gamma

release (and other mediators)

MonocyteMonocyte

Activation

Autocrine Function of IL-2

ActivatedT cell

RestingT cell

Class II MHCAPC

T cell

T cell T cell T cell T cell

T cell T cell T cell T cell

IL2 IL4 IL7

Binds to IL-2 receptor

Receptordecay

Division

Interleukin-4 (IL-4)

• Produced by Th2 cells• Stimulates Ig class switching to IgE

isotype• Stimulates development of Th2 cells

from naïve Th cells• Promotes growth of differentiated Th2

cells

Interleukin-5 (IL-5)

• Produced by Th2 cells• Promotes growth and differentiation of

eosinophils• Activates mature eosinophils• IL-4 and IL-5 can work together Helminths

opsonized with IgE can be killed by activated eosinophils

Interleukin-10 (IL-10)

• Produced by activated macrophages, Th2 cells

• Inhibits production of IFN-γ by Th1 cells needed to activate macrophages

Interferon-gamma (IFN-γ)• Produced by Th cells >> Tc and NK cells

• Numerous functions in both natural and specific immunity

Bcell

MacrophageMacrophageNK

T cell

Th1 cell > Tc cell

NK

Many cell types Many cell types

Induction of class I and class II MHC

Increase in NK

cell activity

Differentiation,Stops cell divisionT cell activation

Weak anti-viral activity,Stops cell division,

Stops hematopoiesis

Activation

GranulocyteGranulocyte

Activation

Endothelial cellActivation

IFN gammasecretion

Stimulators of Hematopoiesis

• Granulocyte-macrophage CSF (GM-CSF) promotes growth and differentiation of bone marrow progenitors

• Macrophage CSF (M-CSF) is involved in development and function of monocytes and macrophages

• Granulocyte CSF (G-CSF) stimulates production of polymorphonuclear leucocytes (PMN)

Colony-Stimulating Factors (CSF)

Cytokines Regulate Ig Class Switching

• Fc region of antibodies determines effector function in different anatomical locations

• Class (isotype) switching produces class or subclass of antibody most effective in host defense

• Cytokines acting alone or in combination regulate class switching

Cytokine Network

• Many cytokines have effects on many cells and organ systems in addition to functions in immune systems

• Referred to as the “cytokine network”

Effects on Cells of Immune System

LymphocyteMacrophageMacrophage

Bcell T cell NK LAK

Proliferation,Differentiation,

Ig secretion and selection

Proliferation,Differentiation,

Cytokineproduction

Activation of cells of immune system Cytokine production

IL1 IL2 IL4

IL1 IL2 IL4 IL5 IL6 IFNγ

cytokines

Cytokine Effects on Organ Systems

Lymphocyte MacrophageMacrophage

Hypothalmus

ACTH

Adrenalgland

Corticosteroid

Liver

Acute phase proteins

Pituitary

IL1 IL6 TNFIL1 IL6 TNF

Fever

-cortisol +

DHEA

IL 6

cytokines

Cytokine Effects on Various Cells

Lymphocyte MacrophageMacrophage

FibrogenesisExtracellular

matrix

cytokines

IL1 TNF

Endothelial cell

Fibroblasts

FibrinogenPermeability change

adhesion

Endothelial cells

cytokines

TNF IL1 IF

Nγ

Hematopoiesis

Bone marrow

IL3 CSFs

cytokines

AngiogenesisFibroblast

Extracellular matrix

Osteoclasts

Tissue remodeling

Tissue repair

IL1

TNF

Anti-viralstate

Many cell types

IL1 TNF IFNα IFNβ IFNγ