Intracellular Inflammatory Regulators

In the preceding sections, the potential role of certain proinflammatory molecules in sleep-wakefulness regulation has been pointed out. However, the brain is an immune-privileged site and has a powerful intrinsic capacity to down-regulate inflammatory processes (for review, see Niederkorn (2006)). In addition, a number of molecules that regulate the intracellular effects of cytokines have been recently defined in the immune system. Some of these molecules have been detected in the nervous system and a short survey of these is given below.

Most cytokines activate membrane receptors that signal via the janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. There are several strategies for a cell to attenuate cytokine signaling to avoid excessive or insufficient signaling, and at least three main classes of intracellular negative regulators that affect components of the JAK/STAT pathway have been identified (Fig. 4.2). These include tyrosine phosphatases (e.g., SH2-containing phosphatases (SHP) that dephosphorylate and thereby deactivate cytokine receptors), protein inhibitors of activated STATs (PIAS), and suppressors of cytokine signaling (SOCS) (for review, see Rakesh and Agrawal (2005)). The SHP and PIAS molecules are expressed constitutively, whereas SOCS molecules are induced in response to cytokines and act as a negative feedback by inhibiting the JAK-STAT signaling cascade.

4.4.2 Intracellular Regulation of Inflammation and the Biological Clock

Given the many effects exerted by cytokines on various cellular elements and regions of the brain, the control of these effects deserves special attention. PIAS1, an inhibitor of activated STAT1 that is a component of the intracellular signaling pathway for IFN-y, is constitutively expressed in the brain but its cellular localization remains to be determined (Maier, Kincaid, Pagenstecher, and Campbell 2002). The SH2-containing phosphatase SHP-1 is expressed in oligodendroglial cells (Massa, Saha, Wu, and Jarosinski 2000) and deficiency of SHP-1 is associated with increased levels of IL-1P in the brain (Zhao and Lurie 2004). A role for SHP-1 in limiting CNS inflammation following injury and disease has therefore been suggested (Zhao et al. 2004). Since cytokine levels can increase dramatically in the brain during inflammatory diseases, the negative feedback regulators SOCS could also play an important role in limiting the response to cytokines. Induction of SOCS has been described in mononuclear cells infiltrating the brain in experimental allergic encephalomyelitis (Campbell 2005), which provides a model for multiple sclerosis, while induction of transcript for SOCS in glial cells and neurons has only rarely been reported (Rosell, Akama, Nacher, and McEwen 2003).

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