TY - JOUR
T1 - CD40-CD40L interactions induce chemokine expression by human microglia
T2 - Implications for human immunodeficiency virus encephalitis and multiple sclerosis
AU - D'Aversa, Teresa G.
AU - Weidenheim, Karen M.
AU - Berman, Joan W.
PY - 2002
Y1 - 2002
N2 - CD40 is a protein on microglia that is up-regulated with interferon (IFN)-γ 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-γ and CD40L increased expression of several chemokines. IFN-γ- 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-γ- 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.
AB - CD40 is a protein on microglia that is up-regulated with interferon (IFN)-γ 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-γ and CD40L increased expression of several chemokines. IFN-γ- 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-γ- 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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U2 - 10.1016/S0002-9440(10)64875-4
DO - 10.1016/S0002-9440(10)64875-4
M3 - Article
C2 - 11839576
AN - SCOPUS:0036173719
SN - 0002-9440
VL - 160
SP - 559
EP - 567
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -