Cytokines And Jakstatcoupled Receptors

There is mounting evidence that many psychiatric disorders may be associated with altered immune function. Even more convincing is the evidence that numerous medical disorders and treatments that regulate immune function are associated with psychiatric symptomatology (Evans et al. 2001). Thus, the mechanism by which the immune system is able to mediate its effects through specified signaling pathways in the CNS will undoubtedly be of increasing importance in our understanding of these complex disorders.

Numerous cytokines and growth factors are able to activate the JAK/STAT pathway; here we focus on interferons as a prototype. Interferons are cytokines that subserve important antiviral, antigrowth, and immunomodulatory activities (Larner and Keightley 2000). The interferon/cytokine receptor family is a group of receptors that, on binding to an extracellular site, produce dimerization or higher-order clustering. Unlike the tyrosine kinase type receptors (Trk), these receptors associate intrinsically in a noncovalent constitutive manner with proteins of the JAK (Janus tyrosine kinase) family to mediate their effects. Signal transducers and activators of transcription (STATs), which are SH2 domain-containing transcription factors, are required for the actions of many other cytokines and growth factors.

There are two types of receptors for which interferons, on binding to the extracellular part of the receptor, are able to rapidly induce corresponding genes: interferon- r.'/B (ifn-l;/B), or type I receptors; and IFN-7, or type II receptors. The interferon-stimulated gene factors, which are more commonly known as STATs, bind to enhancers in the promoter regions of type I and type II receptor genes to mediate transcription (Larner and Keightley 2000). It should be mentioned that in addition to interferon, interleukin-6 and prolactin are other cytokines whose effects have been documented to be mediated by STATs. STATs are modified through tyrosine kinases and are necessary for activation of early response genes on interferon binding to the receptor. Thus, the Janus tyrosine kinases (JAK1-3 and TYK2) are important in the regulation of interferon-mediated cellular effects.

Evidence suggests that IFN-cx/D cluster in receptor complexes, and upon ligand binding, these proteins are able to mediate some of the receptor-effector responses of interferons. Type I interferon receptors consist of two subunits (IFNAR1 and IFNAR2), of which the IFNAR2 subunit has three isoforms (IFNAR2a, IFNAR2b, and IFNAR2c). Upon binding of interferon to IFN-ct, the IFNAR2c subunit is necessary for the activation of the JAK/STAT pathway. Initially, interferons bind to two sites—IFNAR1 and IFNAR2—which heterodimerize, and then the activation of TYK2 and JAK ensues to phosphorylate the receptor (Larner and Keightley 2000). Other phosphatases and kinases are also able to interact with type I interferon receptors to produce a cascade of intercellular effects.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment