LPS induces IL-6 in the brain and in serum largely through TNF production

We investigated the relative contribution of IL-6 and PGE2 directly induced by LPS and indirectly induced via TNF, using in vivo and in vitro models i n the mouse, In these models we have used as tools an anti-TNF antibody and a cyclooxygenase inhibitor, the S enantiomer of ketoprofen (S-KPF), Anti-T NF antibodies inhibited LPS-induced IL-6 production in three different mode ls: IL-6 production by mouse peritoneal macrophages in vitro; serum IL-6 le vels induced by intraperitoneal LPS; and brain IL-6 levels induced by an in tracerebroventricular injection of LPS, However, in vitro anti-TNF antibodi es, did not inhibit LPS-induced PGE2, indicating that this effect is not me diated by TNF. Since PGE2 has an opposite effect on TNF and IL-6 production , inhibiting that of TNF but inducing that of IL-6, we investigated the eff ect of S-KPF on TNF and IL-6 production in vivo following LPS injection. Bo th TNF and IL-6 induction was augmented by S-KPF, but anti-TNF antibodies a bolished the augmentation of IL-6 production. Thus, the effect of anti-infl ammatory drugs on IL-6 production in some models can be secondary to their effect on TNF production. (C) 2000 Academic Press.