Differential regulation of monocytic tumor necrosis factor‐α and interleukin‐10 expression

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Abstract
Activation of human monocytes by bacterial endotoxin (LPS) results in an initial burst of inflammatory cytokines like tumor necrosis factor (TNF)‐α which is followed by the secretion of anti‐inflammatory mediators like interleukin (IL)‐10. The signaling pathways in IL‐10 induction are unknown. Here, we show that the regulation of IL‐10 expression is more complex than that of TNF‐α. LPS‐induced TNF‐α and IL‐10 expression requires early activation of protein tyrosine kinases (PTK). Moreover, delayed addition of PTK inhibitors blocked IL‐10, but not TNF‐α, suggesting the impact of a late PTK activity. Two inducers of PTK activity are the downstream mediators of LPS activation, TNF‐α and cyclic adenosine monophosphate (cAMP). Both mediators synergistically up‐regulate IL‐10 expression. Downstream of PTK activation, they use distinct pathways. TNF‐α, but not cAMP‐induced IL‐10 gene expression was inhibited by pyrrolidine dithiocarbamate, suggesting the involvement of reactive oxygen species. Inhibition of protein kinase C (PKC) suppressed LPS‐induced TNF‐α and IL‐10 expression as well, but, unlike TNF‐α, direct activation of PKC by phorbol 12‐myristate 13‐acetate (PMA) did not induce IL‐10 expression. Furthermore, PKC is not involved in late events of IL‐10 activation, as delayed addition of PKC inhibitors did not suppress LPS‐induced IL‐10 expression and did not influence cAMP‐ or TNF‐α‐induced IL‐10. The modulation of IL‐10 expression by inflammatory mediators suggests a regulatory circuit of the inflammatory response.

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