Chapter 12 Cytokines

Cytokines:

- Any of numerous secreted, low-m-w proteins (usually < 30 kDa) that regulate the intensity and duration of the immune response by exerting a variety of effects on lymphocytes and other immune cells.

- Role in cell-to-cell communication

- Messengers of the immune system

Overview of the Induction and

Function of Cytokines

(Kd ~ 10-10 to 10-12)

Most Cytokines Exhibit Autocrine and/or Paracrine Action; Fewer Exhibit Endocrine Action

Pleiotropy,

Redundancy,

Synergy,

Antagonism

of Cytokines

Cascade Induction of Cytokines

Cytokines, Hormones, and Growth Factors 1. All three are secreted soluble factors that elicit their biological effects at pM concentrations.

2. Growth factors tend to be produced constitutively, whereas cytokine production is carefully regulated. Cytokines are usually secreted after activation of a particular cell, and secretion is short-lived, generally ranging from a few hours to a few days.

3. Hormones generally act long range in an endocrine fashion, most cytokines act over a short distance in an autocrine or paracrine fashion.

Cytokines, Hormones, and Growth Factors

4. Most hormones are produced by specialized glands and tend to have a unique action on one or a few types of target cell. In contrast, cytokines are often produced by a variety of cells and bind to receptors present on numerous types of cells.

Functions of Cytokines

1. Development of cellular and humoral immune responses2. Induction of the inflammatory response3. Regulation of hematopoiesis4. Control of cellular proliferation and differentiation5. Healing of wounds

* Although the immune response to a specific Ag includes the production of cytokines, cytokines act in an Ag-nonspecific manner.

(1)

(2)

(3)

(4)

- Most of the functions of cytokines have been identified from analysis of the effects of recombinant cytokines, often at nonphysiologic concentrations, added individually to in vitro system.- In vivo, however, cytokines rarely, if ever, act alone.- Instead, a target cell is exposed to a milieu ( 環境 ) containing a mixture of cytokines, whose combined syneristic or antagonistic effects can have very different consequences. - Cytokines often induce the synthesis of other cytokines, resulting in cascade of activity.

Cytokine Receptor Families

• Ig superfamily receptors• Class I cytokine receptor family (hematopoietin)3. Class II cytokine receptor family (interferon)4. Tumor necrosis factor (TNF) receptor family5. Chemokine receptor family

3 Subfamilies of Class I Cytokine Receptors

CNTF: ciliary neurotrophic factorLIF: leukemia-inhibitory factorOSM: oncostatin M

Interactions between Cytokine-specific Subunits and a Common Signal-transducing Subunit of

Cytokine Receptors

Competition of Ligand-binding Chains of Different Receptors for a Common Subunit Can Produce

Antagnistic Effects between Cytokines

3 Forms of the IL-2 Receptor

(CD25)

JAK-STAT Signal Transduction Pathways of Cytokine Receptors

JAK: Janus kinases

Stat: signal tranducers and activators of transcription

(lymphotoxin, LT)

TH1 Response

- The TH1 subset is responsible for many cell-mediated functions (e.g., delayed-type hypersensitivity and activation of TC cells) and for the production of opsonization- promoting IgG Abs (i.e., Abs that binds to the high-affinity FcRs of phagocytes and interact with the C system, such as IgG3, IgG1, IgG2). This subset is also associated with the phenomenon of excessive inflammation and tissue injury. - The production of IL-2, IFNand TNF makes the TH1 subset particularly suited to respond to viral infections and intracellular pathogens. IFN also inhibits the expansion of the TH2 population.

TH2 Response

- The TH2 subset stimulates eosinophil activation and differentiation; provides help to B cells, and promotes the production of relatively large amounts of IgM, IgE, and noncomplement-activating IgG isotypes, such as IgG4 in humans and IgG1 in mice. The TH2 subset also supports allergic reactions. The production of Il-4, IL-5 and IL-10 promotes the function of IgE and eosinophils on the anti- helminth (round worm) immunity.

The Regulation of TH Subsets by Cytokines

Correlation between Type of Leprosy ( 痲瘋 ) and Relative TH1 or TH2 Activity