LOW-DOSE LIPOPOLYSACCHARIDE (LPS) PRETREATMENT OF MOUSE MACROPHAGES MODULATES LPS-DEPENDENT INTERLEUKIN-6 PRODUCTION IN-VITRO

Lipopolysaccharide (LPS) can induce mouse macrophages to produce a num ber of cytokines and other inflammatory mediators, Our laboratory prev iously reported that LPS-dependent macrophage-derived tumor necrosis f actor alpha (TNF-alpha) production could be significantly potentiated by pretreatment with LPS at substimulatory LPS priming doses. The obse rved potentiation was shown to be coincident with a down-regulation of LPS-dependent nitric oxide (NO) production (X. Zhang and D. C. Morris on, J. Exp. Med. 177: 511-516, 1993). In order to determine whether th ese LPS reprogramming effects in mouse macrophages were selective for these two macrophage-derived mediators, we have examined the effects o f LPS pretreatment on LPS-dependent interleukin 6 (IL-6) production. T hioglycolate-elicited mouse peritoneal macrophages were pretreated wit h various subthreshold stimulatory concentrations of LPS for 6 h, wash ed three limes, and then stimulated with an effective stimulatory conc entration of smooth LPS for 18 h. In confirmation of earlier studies, pretreatment of mouse macrophages with substimulatory doses of LPS inh ibited the subsequent LPS-dependent NO production, This down-regulatio n was accompanied by a coordinate up-regulation of LPS-dependent IL-6 production, similar to what was shown earlier for TNF-alpha production . These priming effects with the substimulatory dose of smooth LPS are shown to be independent of doses of LPS used for subsequent activatio n and are not restricted to specific LPS stimulation. Moreover, the en hancement of the IL-6 response by LPS pretreatment is still observed i n the presence of neutralizing antibody to TNF-alpha. These findings, therefore, provide further support for the conclusion that LPS-depende nt macrophage reprogramming is likely to involve common regulatory pat hways that control the secretion of both IL-6 and TNF-alpha.