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 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-alpha. LPS-induced TNF-alpha and IL-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 inducers of PTK activity are the downstream mediators of LPS activation, TNF-alpha and cyclic adenosine monophosphate (cAMP). Both mediators synergistically up-regulate IL-10 expression. Downstream of PTK activation, they use distinct pathways. TNF-alpha, 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-alpha and IL-10 expression as well, but, unlike TNF-alpha, 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-alpha-induced IL-10. The modulation of IL-10 expression by inflammatory mediators suggests a regulatory circuit of the inflammatory response.
Meisel
C
C
Institute of Medical Immunology, Medical Faculty Charité, Humboldt-University, Berlin, Germany.
Vogt
K
K
Platzer
C
C
Randow
F
F
Liebenthal
C
C
Volk
H D
HD
D000975:Antioxidants / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011759:Pyrrolidines / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
D000975:Antioxidants; D008070:Lipopolysaccharides; D011759:Pyrrolidines; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C020972:pyrrolidine dithiocarbamic acid; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C