DIFFERENTIAL REGULATION OF MONOCYTIC TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-10 EXPRESSION

Activation of human monocytes by bacterial endotoxin (LPS) results in an initial burst of inflammatory cytokines like tumor necrosis factor (TNF)-alpha which is followed by the secretion of anti-inflammatory me diators like interleukin (IL)-10. The signaling pathways in IL-10 indu ction are unknown. Here, we show that the regulation of IL-10 expressi on is more complex than that of TNF-alpha. LPS-induced TNF-alpha and I L-10 expression requires early activation of protein tyrosine kinases (PTK). Moreover, delayed addition of PTK inhibitors blocked IL-10, but not TNF-alpha, suggesting the impact of a late PTK activity. Two indu cers of PTK activity are the downstream mediators of LPS activation, T NF-alpha and cyclic adenosine monophosphate (cAMP). Both mediators syn ergistically up-regulate IL-10 expression. Downstream of PTK activatio n, they use distinct pathways. TNF-alpha, but not cAMP-induced IL-10 g ene expression was inhibited by pyrrolidine dithiocarbamate, suggestin g the involvement of reactive oxygen species. Inhibition of protein ki nase C (PKC) suppressed LPS-induced TNF-alpha and IL-10 expression as well, but, unlike TNF-alpha, direct activation of PKC by phorbol 12-my ristate 13-acetate (PMA) did not induce IL-10 expression. Furthermore, PKC is not involved in late events of IL-10 activation, as delayed ad dition of PKC inhibitors did not suppress LPS-induced IL-10 expression and did not influence cAMP- or TNF-alpha-induced IL-10. The modulatio n of IL-10 expression by inflammatory mediators suggests a regulatory circuit of the inflammatory response.