Differential effects of endotoxin and cytokines on prostaglandin E2 formation in cerebral microvessels and brain parenchyma: implications for the pathogenesis of fever.
Prostaglandin(PG) E2 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 PGE2 in brain (fever to an external noxa), nor is it clear whether bacterial toxins originating within the brain activate PGE2 directly or via the cytokines (fever to a central noxa). We have previously reported that human interleukin 1 (hIL-1) has no effect on PGE2 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-1 beta (rIL-1 beta and hIL-1 beta), heterologous IL-6 (hIL-6), and endotoxin. The same pyrogens were tested on rat cerebrocortical minces. We have found that PGE2 formation in the microvessels is not changed by either IL-1 beta (both forms) or hIL-6. Conversely, in brain minces rIL-1 beta (but not hIL-1 beta or hIL-6) is a PGE2 activator. Endotoxin stimulated PGE2 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.
Bishai
I
I
Division of Neurosciences, Hospital for Sick Children, Toronto, Ont., Canada.
Coceani
F
F
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism* / Q000503:physiopathology; D002196:Capillaries / Q000378:metabolism*; D002415:Cats; D015232:Dinoprostone / Q000096:biosynthesis*; D004731:Endotoxins / Q000008:administration & dosage*; D005334:Fever / Q000209:etiology / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000008:administration & dosage*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D015232:Dinoprostone