IL-4 AND IL-10 MODULATION OF CD40-MEDIATED SIGNALING OF MONOCYTE IL-1-BETA SYNTHESIS AND RESCUE FROM APOPTOSIS

Previous studies have demonstrated that the interaction of CD40 on mon ocytes with SD40 ligand, present on activated CD4(+) T cells, induces monocyte inflammatory cytokine synthesis and rescues monocytes from ap optosis, These findings suggest a role for CD40 signaling of monocyte activation in the maintenance and/or exacerbation of nonseptic (e.g., autoimmune) inflammatory responses, In the present study the effects o f the modulatory cytokines IL-4 and IL-l0 on CD40-mediated signaling o f monocyte IL-1 beta synthesis and rescue from apoptosis were examined , Both IL-4 and IL-10 decreased CD40-dependent IL-1 beta synthesis in a dose-dependent manner individually and synergized in this effect whe n used concurrently, with minimal effect on CD40 surface expression, C D40 signaling of IL-1 beta synthesis was shown to be dependent on the induction of protein tyrosine kinase (PTK) activity, and both IL-4 and IL-10 diminished CD40-mediated tyrosine phosphorylation of monocyte c ellular proteins, However, IL-4, but not 1L-10, blocked CD40-mediated rescue from apoptosis, an event that we have demonstrated previously t o be dependent on PTK activity as well, Together these results suggest that in monocytes 1) both IL-4 and IL-10 target CD40-induced PTK acti vity in the down-regulation of IL-1 beta synthesis; and 2) 1L-4 and IL -10 have divergent effects on the CD40 signaling pathway, in that thes e cytokines are synergistic with respect to their abilities to inhibit CD40-mediated IL-1 beta synthesis and differ in their abilities to bl ock CD40-mediated rescue from apoptosis.