DIFFERENTIAL EFFECTS OF ENDOTOXIN AND CYTOKINES ON PROSTAGLANDIN E2FORMATION IN CEREBRAL MICROVESSELS AND BRAIN PARENCHYMA: IMPLICATIONS FOR THE PATHOGENESIS OF FEVER

Abstract Prostaglandin(PG) E 2 is regarded as an essential mediator in the central action of pyrogens and fever. However, it is not clear how the appearance of cytokines in the circulation leads to the rise of PGE 2 in brain (fever to an external noxa), nor is it clear whether bacterial toxins originating within the brain activate PGE 2 directly or via the cytokines (fever to a central noxa). We have previously reported that human interleukin 1 (hIL-1) has no effect on PGE 2 synthesis in isolated, feline cerebral microvessels. Since cytokine action may be species-specific and interleukin 6 (IL-6) is considered as important as IL-1 for fever, we have now examined the response of isolated, murine cerebral microvessels to homologous and heterologous IL-1β (rIL-1β and hIL-1β), heterologous IL-6 (hIL-6), and endotoxin. The same pyrogens were tested on rat cerebrocortical minces. We have found that PGE 2 formation in the microvessels is not changed by either IL-1β (both forms) or hIL-6. Conversely, in brain minces rIL-1β(but not hIL-1β or hIL-6) is a PGE 2 activator. Endotoxin stimulated PGE 2 synthesis in both preparations and its action in brain was fully reversed by the hIL-1 receptor antagonist (hIL-1ra). Our data indicate that the cerebral microvasculature does not lend itself to a transducing function in the fever to an external noxa. In addition, they point to a mediator role of IL-1 in the fever to a central noxa.