Chemokines and chemokine receptors in inflammation of the nervous system: manifold roles and exquisite regulation

This article focuses on the production of chemokines by resident glial cell s of the nervous system. We describe studies in two distinct categories of inflammation within the nervous system: immune-mediated inflammation as see n in experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS) and post-traumatic inflammation. We provide evidence that chemokines p lay a role in amplifying the inflammatory reaction in EAE land, probably, ( MS). In the context of neural trauma, chemokines appear to be primary stimu li for leukocyte recruitment. Strikingly, expression of monocyte chemoattra ctant protein (MCP)-1 and interferon-gamma -inducible protein-10 (IP-10) ar e largely restricted to astrocytes or other glial cells in these diverse pa thological states. The remainder of the review focuses on studies that addr ess the molecular mechanisms which underlie transcriptional regulation of t hree astrocyte-derived chemokines: MCP-1, IP-10 and beta -R1/interferon-gam ma -inducible T-cell chemoattractant (I-TAC). Based on these studies, we pr opose that the complex promoters of these genes are marvelously organized f or flexible and efficient response to challenge. In the case of MCP-1, seve ral different stimuli can elicit gene transcription, acting through a conse rved mechanism that includes binding of inducible transcription factors and recruitment of the constitutive factor Sp1. For IP-10 and beta -R1-TAC, it appears that efficient gene transcription occurs only in highly inflammato ry circumstances that produce aggregates of simultaneous stimuli. These cha racteristics, in turn, mirror the expression patterns of the endogenous gen es: MCP-1 is expressed under a variety of circumstances, while IP-10 appear s primarily during immune-mediated processes that feature exposure of resid ent neuroglia to high levels of inflammatory cytokines.