DIFFERENTIAL-EFFECTS OF IL-6 ON SYSTEMIC AND CENTRAL PRODUCTION OF TNF - A STUDY WITH IL-6-DEFICIENT MICE

Interleukin 6 (IL-6) is known to inhibit the synthesis of tumour necro sis factor (TNF) in vitro and in vivo, In this study we investigated t he possible role of IL-6 as an endogenous inhibitor of TNF production in the brain or in the periphery using IL-6-deficient mice or administ ering recombinant human IL-6 (rhIL-6), When IL-6-deficient mice were i njected intracerebro-ventricularly (i.c.v.) with lipopolysaccharide (L PS), no differences were observed in the production of TNF in the brai n, while in the periphery (serum or spleen) TNF levels were markedly i ncreased (about four-fold), When normal mice were injected i.c.v. with a combination of LPS and rhIL-6, inhibition of TNF production was onl y slight (about 20%), while IL-6 had a stronger effect (> 80% inhibiti on) in the periphery, Go-administration of soluble IL-6 receptor (sIL- 6R) did not enhance the effect of IL-6 on brain TNF,so this refractori ness cannot be attributed to a lack of IL-6 receptors, Interestingly, IL-6 potently inhibited LPS-induced TNF production by macrophagic cell s but not by a microglial cell clone, suggesting that the defective re sponse to IL-6 of the brain lies within tile responsiveness TNF produc ing cells to IL-6, It thus appears that the TNF-inhibitory role of IL- 6 is confined to the periphery. (C) 1997 Academic Press Limited.