LIPOPOLYSACCHARIDE-INDUCED INTERLEUKIN-10 IN MICE - ROLE OF ENDOGENOUS TUMOR-NECROSIS-FACTOR-ALPHA

Interleukin (IL)-10 is known to protect mice against the lethal effect s of lipopolysaccharides (LPS) and is considered to be an anti-inflamm atory cytokine which suppresses the production of pro-inflammatory cyt okines. We have examined the interactions of the pro-inflammatory cyto kine tumor necrosis factor-alpha (TNF-alpha) with IL-10. Neutralizatio n of TNF-alpha in murine bone marrow-derived macrophages resulted in a significant reduction of LPS-inducible IL-10 production. In mice, inj ection of 5 mg/kg LPS induced circulating IL-10 with a biphasic time c ourse exhibiting an early peak 1.5 h after challenge (synchronous with TNF-alpha) and, after a nadir at 6 h, a second increase between 8 and 12 h. Treatment of mice with neutralizing anti-mouse TNF-alpha antise rum significantly increased LPS-induced IL-10 plasma levels between 1. 5 and 6 h but diminished those at 12 h, while circulating IL-6, interf eron-gamma (IFN-gamma) and granulocyte colony-stimulating factor (G-CS F) concentrations were attenuated overall, without a biphasic response . Analysis of LPS-induced IL-10 mRNA expression in different tissues 1 h and 8 h after LPS or LPS plus anti-TNF-alpha revealed that the amou nt of transcripts in the liver correlated with circulating early and l ate IL-10 levels. Our findings suggest that endogenous TNF-alpha down- regulates the early and up-regulates the late LPS-induced IL-10 synthe sis in vivo and that the liver is the major source of circulating IL-1 0 after stimulation with LPS.