C. Meisel et al., DIFFERENTIAL REGULATION OF MONOCYTIC TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-10 EXPRESSION, European Journal of Immunology, 26(7), 1996, pp. 1580-1586
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.