Am J Pathol 2002 Feb;160(2):559-567
D'Aversa TG, Weidenheim KM, Berman JW.
Departments of Pathology andMicrobiology and Immunology, 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.