CD40-CD40L interactions induce chemokine expression by human microglia: implications for human immunodeficiency virus encephalitis and multiple sclerosis.
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.
D'Aversa
Teresa G
TG
Department of Pathology, Albert Einstein College of Medicine, Forchheimer 727, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Weidenheim
Karen M
KM
Berman
Joan W
JW
D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002648:Child; D018792:Encephalitis, Viral / Q000503:physiopathology*; D005260:Female; D015658:HIV Infections / Q000276:immunology / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009103:Multiple Sclerosis / Q000276:immunology / Q000503:physiopathology; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D019013:CD40 Antigens; D023201:CD40 Ligand; D018925:Chemokines; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; C067980:CD68 antigen, human; D000097382:CD68 Molecule