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Ligation of Microglial CD40 Results in p44/42 Mitogen-Activated Protein Kinase-Dependent TNF- Production That Is Opposed by TGF-ß1 and IL-10

The Roskamp Institute, Department of Psychiatry, University of South Florida, Tampa, FL 33613

Recently, it has been demonstrated that the CD40 receptor is constitutively expressed on cultured microglia at low levels. Ligation of CD40 by CD40 ligand on these cells results in microglial activation, as measured by TNF- production and neuronal injury. However, the intracellular events mediating this effect have yet to be investigated. We report that ligation of microglial CD40 triggers activation of p44/42 mitogen-activated protein kinase (MAPK). This effect is evident 30 min posttreatment, and progressively declines thereafter (from 30 to 240 min). Phosphorylated p38 MAPK is not observed in response to ligation of microglial CD40 across the time course examined. Inhibition of the upstream activator of p44/42 MAPK, mitogen-activated protein/extracellular signal-related kinase kinase 1/2, with PD98059, decreases phosphorylation of p44/42 MAPK and significantly reduces TNF- release following ligation of microglial CD40. Furthermore, cotreatment of microglial cells with CD40 ligand and TGF-ß1 or IL-10, or both, inhibits CD40-mediated activation of p44/42 MAPK and production of TNF- in a statistically interactive manner. Taken together, these data show that ligation of microglial CD40 triggers TNF- release through the p44/42 MAPK pathway, an effect that can be opposed by TGF-ß1 and IL-10.

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