Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells.

Abstract Fever induced by endogenous as well as exogenous pyrogens is often prevented by cyclooxygenase inhibitors; endogenous pyrogens stimulate prostaglandin E 2 (PGE 2 ) in or near the thermoregulatory centers of the brain. The cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF), are two pyrogens which stimulate brain PGE 2 formation during fever and also increase PGE 2 synthesis in human mononuclear cells in vitro. In the present study, we examined whether interleukin-6 (IL-6) stimulates PGE 2 formation in a manner similar to IL-1 and TNF. Both glycosylated and non-glycosylated forms of recombinant human IL-6 were tested. Following intravenous injection into rabbits, the glycosylated IL-6 was more pyrogenic than the non-glycosylated form and there was no evidence of synergy in the production of fever when IL-6 and IL-1 were given simultaneously. IL-6 fever was blocked by prior administration of the cyclooxygenase inhibitor ibuprofen. IL-6 was also pyrogenic in the cat by either the systemic or the intraventricular route. However, in both species, IL-6 was less effective than IL-1s. When given intraventricularly to cats, IL-6 produced an increase in PGE 2 levels of the cerebrospinal fluid in parallel with the rise in body temperature. In the latter respect, IL-6 imitated IL-1s; however, IL-6 from 0.15–15 μg/ml did not increase mononuclear cell PGE 2 production in vitro whereas IL-1s induced 20–30-fold increases in PGE 2 at 100 ng/ml. These results suggest that IL-6, similar to IL-1 and TNF, causes fever via the rapid increase in brain PGE 2 synthesis but unlike IL-1, stimulation of PGE 2 in mononuclear cells was not observed by IL-6.