CD45 inhibits CD40L-induced microglial activation via negative regulation of the Src/p44/42 MAPK pathway.
It has been reported that ligation of CD40 with CD40 ligand (CD40L) results in microglial activation as evidenced by p44/42 mitogen-activated protein kinase (MAPK) dependent tumor necrosis factor alpha (TNF-alpha) production. Previous studies have shown that CD45, a functional transmembrane protein-tyrosine phosphatase, is constitutively expressed at moderate levels on microglial cells and this expression is greatly elevated on activated microglia. To investigate the possibility that CD45 might modulate CD40L-induced microglial activation, we treated primary cultured microglial cells with CD40L and anti-CD45 antibody. Data show that cross-linking of CD45 markedly inhibits CD40L-induced activity of the Src family kinases Lck and Lyn. Further, co-treatment of microglia with CD40L and anti-CD45 antibody results in significant inhibition of microglial TNF-alpha production through inhibition of p44/42 MAPK activity, a downstream signaling event resulting from Src activation. Accordingly, primary cultured microglial cells from mice deficient in CD45 demonstrate hyper-responsiveness to ligation of CD40, as evidenced by increased p44/42 MAPK activation and TNF-alpha production. Taken together, these results show that CD45 plays a novel role in suppressing CD40L-induced microglial activation via negative regulation of the Src/p44/42 MAPK cascade.
Tan
J
J
Roskamp Institute, Department of Psychiatry, University of South Florida, Tampa, Florida 33613, USA. jtan@com1.med.usf.edu
Town
T
T
Mullan
M
M
D000544:Alzheimer Disease / Q000503:physiopathology; D000818:Animals; D023201:CD40 Ligand / Q000494:pharmacology*; D000081247:CSK Tyrosine-Protein Kinase; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D017493:Leukocyte Common Antigens / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000503:physiopathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019061:src-Family Kinases
D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens