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(American Journal of Pathology. 2002;160:559-567.)
© 2002 American Society for Investigative Pathology

Regular Articles

CD40-CD40L Interactions Induce Chemokine Expression by Human Microglia

Implications for Human Immunodeficiency Virus Encephalitis and Multiple Sclerosis

Teresa G. D’Aversa*, Karen M. Weidenheim* and Joan W. Berman*{dagger}

From the Departments of Pathology*
andMicrobiology and Immunology,{dagger}
Albert EinsteinCollege of Medicine, Bronx, New York

CD40 is a protein on microglia that is up-regulated with interferon (IFN)-{gamma} and is engaged by CD40L, found on CD4+ T cells, B cells, and monocytes. These interactions may be important in central nervous system inflammatory diseases. Microglia have been shown to be a source of chemokines, whose expression plays a key role in central nervous system pathologies. We examined the expression of CD40 on microglia in human immunodeficiency virus (HIV) encephalitic brain, and the effects of CD40-CD40L interactions on the expression of chemokines by cultured microglia. We found significantly increased numbers of CD40-positive microglia in HIV-infected brain tissue. Treatment of cultured microglia with IFN-{gamma} and CD40L increased expression of several chemokines. IFN-{gamma}- and CD40L-induced MCP-1 protein was mediated by activation of the ERK1/2 MAPK pathway, and Western blot analysis demonstrated phosphorylation of ERK1/2 upon stimulation of microglia. In contrast, IFN-{gamma}- and CD40L-induced IP-10 protein production was mediated by the p38 MAPK pathway. Our data suggest a mechanism whereby CD40L+ cells can induce microglia to secrete chemokines, amplifying inflammatory processes seen in HIV encephalitis and multiple sclerosis, and implicate CD40-CD40L interactions as a target for interventional strategies.




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