TNF RECEPTOR P55 PLAYS A MAJOR ROLE IN CENTRALLY MEDIATED INCREASES OF SERUM IL-6 AND CORTICOSTERONE AFTER INTRACEREBROVENTRICULAR INJECTION OF TNF

The aim of this work was to study the relative role of the two TNF rec eptors (p55 and p75) in the central actions of TNF, studying the eleva tion of serum corticosterone (CS) and IL-6 levels after injection of r ecombinant murine (rm)TNF (intracerebroventricularly (i.c.v.)) in norm al or p55-deficient (p55 -/-) mice. rmTNF induced high serum IL-6 leve ls and doubled serum CS in normal mice, whereas no elevation of serum IL-6 or CS was induced in p55 -/- mice. However, a normal CS response was observed in p55 -/- mice after LPS (2.5 mu g, i.c.v.). p55 -/- mic e also responded, although to a lesser extent than p55 +/+, in terms o f LPS-induced IL-6 production. We also injected two agonist Abs specif ic for the two receptors, (alpha p55 and alpha p75. While alpha p55 in jected i.c.v. induced a marked elevation in CS and IL-6, alpha p75 ind uced CS (although less than alpha p55) but no IL-6. rmTNF, which binds both receptors, was more potent in inducing IL-6 and CS than injectio n of rhTNF, which in mice binds only p55. Finally, we investigated the role of p55 and p75 in IL-6 induction by TNF in a murine brain endoth elioma. The results resembled closely those obtained in vivo: rmTNF wa s more potent than rhTNF and only alpha p55, and not alpha p75, induce d IL-6 production. These data indicate that p55 plays a major role in TNF activation of the hypothalamus-pituitary-adrenal axis and in the c entrally mediated induction of peripheral IL-6 by TNF, but p75, despit e having little IL-6 inductive properties by itself, seems to potentia te p55 induction of IL-6.