Cytokine Receptors And Signaling

Cytokines, the secreted "messenger molecules" of the immune system, were introduced in Chapter 1 and discussed in Chapter 4 in the context of innate immunity; their roles in adaptive T cell-mediated immune responses will be described in Chapters 9 and 10. Here we will describe receptors for cytokines and their mechanisms of signaling.

All cytokine receptors consist of one or more transmembrane proteins whose extracellular portions are responsible for cytokine binding and whose cytoplasmic portions are responsible for initiation of intracellular signaling pathways. For most cytokine receptors, these signaling pathways are typically activated by ligand-induced receptor clustering, bringing together the cyto-plasmic portions of two or more receptor molecules, thus inducing the activity of unique non-receptor tyrosine kinases. In the case of the TNF receptor family of cytokine receptors, preformed receptor trimers apparently undergo a conformational change after contacting their cognate trimeric ligands.

Classes of Cytokine Receptors

The most widely used classification of cytokine receptors is based on structural homologies of the extracellular cytokine-binding domains and shared intracellular signaling mechanisms (Fig. 7-23). Signaling through type I and type II cytokine receptors occurs by a similar mechanism, known as JAK-STAT signaling, that is described in more detail later. Cytokine receptors of the TNF receptor family activate a number of pathways, a prominent one being the NF-kB pathway, which will also be considered in detail later. Signaling through the IL-1R and the TLR families uses a common cytoplasmic domain, and a major component downstream is ubiquitin E3 ligase-dependent activation of the NF-kB pathway. Chemokines, which

Cytokine receptor families

Type I cytokine Type II cytokine TNF receptor family IL-1 receptor (hemopoietin) receptors ^ ^ ,-j family receptors

Conserved cysteines

WSXWSxl

Conserved cysteines

WSXWSxl

-Jak r STAT

-Jak r STAT

Ligands: IL-2, IL-3, IL-4, IL-5, IL-6,IL-7,IL-9,IL-11 IL-12, IL-13, IL-15, GM-CSF, G-CSF

Ligands: IFN-a/ß, IFN-y IFN-À, IL-10, IL-20, IL-24, IL-26

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