DIFFERENTIAL-EFFECTS OF ENDOTOXIN AND CYTOKINES ON PROSTAGLANDIN E(2)FORMATION IN CEREBRAL MICROVESSELS AND BRAIN PARENCHYMA - IMPLICATIONS FOR THE PATHOGENESIS OF FEVER

Prostaglandin(PG) E(2) is regarded as an essential mediator in the cen tral action of pyrogens and fever. However, it is not clear how the ap pearance of cytokines in the circulation leads to the rise of PGE(2) i n brain (fever to an external nora), nor is it clear whether bacterial toxins originating within the brain activate PGE(2) directly or via t he cytokines (fever to a central nora), We have previously reported th at human interleukin 1 (hIL-1) has no effect on PGE(2) synthesis in is olated, feline cerebral microvessels, Since cytokine action may be spe cies-specific and interleukin 6 (IL-6) is considered as important as I L-1 for fever, we have now examined the response of isolated, murine c erebral microvessels to homologous and heterologous IL-1 beta (rIL-1 b eta and hIL-1 beta), heterologous IL-6 (hIL-6), and endotoxin. The sam e pyrogens were tested on rat cerebrocortical minces, We have found th at PGE(2) formation in the microvessels is not changed by either IL-1 beta (both forms) or hIL-6. Conversely, in brain minces rIL-1 beta (bu t not hIL-1 beta or hIL-6) is a PGE(2) activator. Endotoxin stimulated PGE(2) synthesis in both preparations and its action in brain was ful ly reversed by the hIL-1. receptor antagonist (hIL-1ra). Our data indi cate that the cerebral microvasculature does not lend itself to a tran sducing function in the fever to an external nora, In addition, they p oint to a mediator role of IL-1 in the fever to a central noxa. (C) 19 96 Academic Press Limited