CD40 signaling of monocyte inflammatory cytokine synthesis through an ERK1/2-dependent pathway - A target of interleukin (IL)-4 and IL-10 anti-inflammatory action

Ligation of CD40 on monocytes through its interaction with CD40 ligand (CD1 54) present on activated T helper cells, results in activation of monocyte inflammatory cytokine synthesis and rescue of monocytes from apoptosis indu ced through serum deprivation, Both of these consequences of CD40 stimulati on have been shown to be dependent on the induction of protein tyrosine kin ase activity, CD40-mediated activation of protein tyrosine kinase activity and subsequent inflammatory cytokine production are abrogated by treatment of monocytes with the T helper type 2 cytokines interleukin 4 (IL-4) and in terleukin 10 (IL-10), In the current study we demonstrate that stimulation of monocytes through CD40 resulted in the phosphorylation and activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activa ted protein kinases, whereas phosphorylation of mitogen-activated protein k inases family members p38 and c-Jun N-terminal kinase was not observed in r esponse to this stimuli over the time course examined, PD98059, an inhibito r of the upstream activator of ERK1/2, the MAP/ERK kinase MEK1/2, suppresse d IL-1 beta and tumor necrosis factor-alpha production in a dose-dependent fashion, Pretreatment of monocytes with IL-4 and IL-10 inhibited CD40-media ted activation of ERK1/2 kinase activity when used individually, and are en hanced in effectiveness when used in combination. Together, the data demons trate that CD40-mediated induction of IL-1 beta and tumor necrosis factor-a synthesis is dependent on a MEK/ERK pathway which is obstructed by signals generated through the action of IL-4 and IL-10.