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Home , Chemokine, Cytokine, Cytokine receptor, Interleukin, Ligand (biochemistry), TNF receptor superfamily

Chapter 13: - Cytokines act only on cells bearing specific receptors.

Definition: secreted, low-molecular-weight that - Expression of cytokines and regulate the nature, intensity and duration of the immune their receptors is highly response by exerting a variety of effects on and/or regulated . other cells. - E.g. IL-2 - Cytokines bind to specific receptors on target cells.

- Originally were called because they were initially thought to be produced only by lymphocytes. Then because they were secreted by and . Then because they are produced by some leukocytes and affect other leukocytes. The term “” is now used more widely and covers all of the above.

- Don’t forget , they are also considered cytokines.

Cytokines can act in an: 1. Cytokines are pleiotropic … one cytokine can have - Autocrine (same ), different effects on different cells. - Paracrine (close proximity) - Endocrine (long distance)

2. Cytokines can be redundant … different cytokines can 3. Cytokines can synergize with each other. have the same effects.

Kuby Fig 12-2a

1 4. Cytokines can antagonize each other. 5. Cascade effect , cytokines can stimulate the production of other cytokines.

IgG1

Th

IgG2a or IgG3

Figure 10.5a

6. Cytokines can influence the expression of cytokine 7. Cytokines play key roles in regulating hematopoiesis , receptors . innate and acquired immunity .

Positive Negative

Figure 10.5b Figure 10.4c

Sandwich ELISA SO…cytokines can have many effects, depending on:

- the target cell - the state of differentiation/ of the target cell - the presence or absence of other cytokines Cytokine levels in serum or in tissue culture supernatants can be measured with a Sandwich ELISA .

2 There are many cytokines, including... Four Structural Families

IL-1 IL-2 IL-3 IL-4 • Hematopoietin Family (IL-2, IL-4) IL-5 IL-6 IL-7 IL-8 IL-9 IL-10 IL-11 IL-12 • Family (IFN-α, β, γ) IL-13 IL-15 IL-16 IL-17 IL-18 IL-19 IL-20 IL-21 • Family IL-22 IL-23 • Tumor family IFN-ααα IFN-βββ IFN-γγγ

TNF-ααα TNF-βββ

TGF-βββ1

M-CSF G-CSF GM-CSF

Based on structural homology, there are six major families :

Best way to learn - Ig superfamily receptors about cytokines…. is - Interferon receptors by their action !!! - TNF receptor superfamily

- Chemokine receptors

- TGF receptor family

- Hematopoietin receptors (Cytokine receptor superfamily)

(b)

Kuby Fig 12-6b

Kuby Fig 12-6a

3 b (d) LIGANDS LIGANDS

and others

Fig 12-6d

Kuby Fig 12-6c

Three subfamilies of the class I cytokine receptor family (hematopoietin)

4 SHARED CYTOKINE RECEPTORS SUBUNITS

(CD25)

Cytokine receptors 1. Cytokine binds to alpha subunit. • Sharing of signal transducing molecules explains the redundancy and 2. Association with exhibited by some cytokines beta subunit. 3. through the beta subunit

Competition of IL-2 Receptor -binding chains of • Composed of 3 subunits: α, β, and γ chains different receptors for a • IL-2 receptor is present in 3 forms: low, common subunit. medium, and high affinity • The low affinity (monomeric, IL-2R α), This can medium affinity (dimeric, IL-2R αβ), and results in antagonistic high affinity (trimeric, IL-2R αβγ) effects • Binding component: α chains between cytokines • Transducing components: β and γ chains .

5 A number of cytokine receptors signal via the JAK/STAT pathway.

These include the receptors for IL- 2, IL-3, IL-4, IL-6, IL-10, IL-12 and IFN-γγγ.

Cytokine receptor subunits are Only in activated associated with JAK kinases . T cells 1.- Binding of cytokine causes dimerization of receptors and activation of JAK kinases .

2.- Activated JAK kinases phosphorylate receptor sites and create sites for STAT molecules.

JAK = - OR - Just Another Kinase

STAT = Signal Transducers and Activators of Transcription

3. After binding to the receptor ( ααα chain), STATs Similar JAK/STAT are phosphorylated. signaling in the IL-4 receptor. 4. They then dissociate from the receptor, dimerize and translocate to the nucleus, where they mediate transcription of target .

Kuby Fig 12-10b

Different receptors associate with different JAK/STAT combinations Other pathways may also be involved in cytokine signaling.

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6 Helper T cells can be divided

into two main types - TH1 and TH2 - with distinct patterns of cytokine secretion.

TH1 cells produce cytokines (IFN-γγγ and IL-2) that TH1/T H2 differentiation is influenced by the levels of key promote immune responses against intracellular cytokines. pathogens ( DTH, cytotoxic responses, - IL-4 promotes T 2 differentiation. opsonizing Abs ). H

- IFN-γγγ and IL-12 promotes T H1 differentiation. IL-12R = β1, β2 TH2 cells produce cytokines (IL-4, IL-5, IL-6, IL-13) that promote immune responses against extracellular pathogens ( responses, eosinophilic responses, allergic reactions).

Some cytokines are produced by both T H1 and T H2 cells. These cytokines - GM-CSF and IL-3 - act on the marrow to increase production of leukocytes - so they are needed no matter what type of pathogen is present.

Figure 10.7

Cytokine cross-regulation Cytokine & Diseases

• IFN-γ (Th-1) inhibits proliferation of Th-2 • Bacterial • IL-4 and IL-10 (Th-2) inhibits proliferation – Due to several Gram (-) – Stimulation of Macrophages by LPS  ↑ TNF-α, IL-1β of Th-1 by decreasing IL-12 production – Drop in pressure, , diarrhea, systemic blood clotting in • INF-γ (Th-1) promotes IgG2a production various organs and decreases IgE by B cells • Bacterial Toxic Shock – Caused by (wide variety of toxins) • IL-4 (Th-2) promotes production of IgE and – Activation of T cells  ↑ cytokines from T cells and activated MØ IgG1 by B cells and decreases IgG2a . • Infectious Diseases – Leprosy, .

7 Relative predominance of T H1 vs TH2 helper T cells can influence the course of infectious disease ( Mycobacterium leprae ) Neuroendocrine regulation

IL-1, IL-6 and TNF-ααα can induce production of by acting on the hypothalamic- pituitary-adrenal (HPA) axis.

Tuberculoid - ↑ CMI () Lepromatous - ↑ HI (dissemination) - No RIP - RIP Figure 11.19

Glucocorticoid can influence ongoing The End, but interesting immune responses - particularly suppressing material next!! inflammatory responses.

Sex hormones also influence immune responses - e.g. females tend to be more prone to autoimmune disorders than males.

Stress may suppress Th1 immune responses.

Figure 11.20

Macrophage activation by Th1 Cells: activation by Th2 Cells: Ab?

Ab?

8 ROLE OF EFFECTOR ROLE Th1 CELLS: OF Th2 CELLS: 1) Cytotoxicity 1) IgE production 2) ↑ Phagocytosis 3) ↑ opzonizing & 2) IgA production complement 3) recruitment fixing Abs 4) & recruitment

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