Chemokine and chemokine receptors: Role in inflammation of the central nervous system
McManus, Carrie Margaret
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Neuroimmunologic diseases are characterized by activation of cells endogenous to the central nervous system (CNS), release of inflammatory mediators, as well as marked recruitment of inflammatory cells to the site of injury. This inflammation can be manifest by numerous clinical symptoms, as seen in multiple sclerosis (MS) and HIV encephalitis. Chemokines, chemotactic cytokines, act to selectively recruit cells to sites of jury. Chemokines act through specific binding of a class of seven-transmembrane, G-protein coupled receptors. We are studying chemokines and their receptors in the CNS with the goal of understanding their role in the pathogenesis of neroinflammatory diseases. Microglia, resident brain macrophages, and astrocytes are important immune cells of the CNS. We demonstrate that cultured human glial cells produce chemokines. Analysis of cultured primary human fetal microglia shows the product ion of the C-C chemokines, MIP-1alpha, MIP-1beta, and MCP-1 after treatment with TNF-alpha and IL-1beta, but not IFN-gamma and that these chemokines are potently induced by endotoxin. Astrocytes differ from microglia in that they only produce MCP-1 in response to proinflammatory cytokines and do not respond to endotoxin. Transforming growth, factor beta, (TGF-beta), a cytokine shown to downregulate chemokine production in cells of the periphery, had no effect on microglial expression of chemokines. Using immunohistochemistry and in situ hybridization techniques, brain sections from MS patients were examined for the expression of MCP-1, -2, -3, MIP-1alpha, and MIP-1beta. Results showed that MCP-1, -2, -3 are all expressed in different types of MS lesions but not in control brains. There was no evidence for the expression of MIP-1alpha or MIP-1beta protein in these lesions. Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, has been used to study the function of chemokines in the disease process. IL-4, a Th2 cytokine, is thought to play a protective role in EAE and without IL-4 animals have a more severe disease course than wildtype animals. We find significant differences in chemokine and chemokine receptor expression between wildtype and IL-4 knockout mice indicating an important role for IL-4 in the regulation of chemokines. These data support our hypotheses that chemokines are expressed by glial cells and that this expression is upregulated during inflammation.;Specific C-C chemokine receptors have been shown to play a crucial role in HIV infection. The virus utilizes these as coreceptors with CD4 for entry into target cells. HIV encephalitis is characterized by inflammatory infiltrates into the CNS with motor and cognitive dysfunction. Examination of pediatric HIV encephalitis tissue shows the expression of chemokines and their receptors in the CNS of these patients. HIV infection of cells results in the production of HIV specific proteins including Tat the HIV transactivator protein. Tat is secreted from HIV-infected cells. We examined the effects of Tat on primary human fetal astrocytes and microglia and found Tat to be a significant inducer of chemokines in both cell types. It is important to understand the mechanism by which the inflammatory response may be perpetuated in neuroimmunologic diseases. Treatment of microglia and astrocytes with chemokines results in the production of chemokines. This expression is time and dose dependent as well as being chemokine specific. The effects of chemokines on their receptors were also analyzed. Astrocytes do not have mRNA expression of any CC chemokine receptors and chemokine treatment of microglia has no significant effects on C-C chemokine receptor mRNA levels. Understanding the expression and regulation of chemokines and their receptors will aid in the development of therapeutic strategies for the treatment of inflammatory diseases of the CNS.
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