Inhibition of CD40 signaling pathway by tyrphostin A1 reduces secretion of IL-12 in macrophage, Th1 cell development and experimental allergic encephalomyelitis in SJL/J mice

Activation of antigen presenting cells through the interaction of CD40 with its ligand is a critical co-stimulatory signal for IL-12 production and Th1 differentiation. Tyrphostins are organic molecules that inhibit the phosphorylation of protein tyrosine kinases. We show that tyrphostin Al inhibits CD40L-stimulated IL-12 production in macrophage cultures and antigen-induced generation of Th1 cells. Our data also show that tyrphostin Al blocks CD40L-induced translocation of NF-KB to the nucleus, and reduces the activation of IL-12 p40 gene. In vivo therapy with AZ leads to decrease in generation of myelin basic protein (MBP) specific encephalitogenic T cells. In addition, treatment of SJL/J mice with Al results in attenuation of experimental allergic encephalomyelitis (EAE). (C) 2001 Elsevier Science B.V. All rights reserved.