Central injections of prostaglandin activate the hypothalamus and suppress splenic cytokine production

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Pan, Li
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Since the central activational effects of the pro-inflammatory cytokine IL-1 beta, as well as endotoxin, have been shown to be blocked by the cyclooxygenase inhibitor indomethacin, we have tested whether central injections of prostaglandin-2 (PGE2) suppress the production of splenic cytokine in vivo following an endotoxin challenge. In the first experiment, adult male rats were implanted unilaterally with an intracerebroventricular (ICV) cannula in the lateral ventricle. One week later, rats received ICV injections of a long-acting PGE2 analogy (15-methyl PGE2; 4 $\mu$g) in 20 $\mu$l, or saline. Thirty min after the ICV injection, all rats received an IV injection of endotoxin (0.1 $\mu$g LPS) and were killed one hour later. The spleens were removed and rapidly frozen and the rats were then perfused with fixative. The brains were processed for the immunocytochemical localization of c-fos protein, whereas the production of splenic cytokines was quantified by Northern blotting with digoxigenin-labelled riboprobes. Relative to saline injected controls, PGE2 injections produced a significant and dramatic increase in the number of c-fos protein positive neurons in the paraventricular nuclei (PVN) and supraoptic nuclei (SON) of the hypothalamus. Analysis of splenic levels of TNF-alpha and IL-1 beta mRNA indicated that PGE2 produced a significant decrease in TNF-alpha mRNA. However, IL-1 beta mRNA levels were comparable between the PGE2 and saline injected groups. In the second experiment, the rats were divided into two groups composed of sham surgeries and splenic nerve sections. Rats were given an ICV injection of the PGE2 (4$\mu$g in 20 $\mu$l saline) and 30 minutes later injected iv with 0.1 $\mu$g LPS. Cutting the splenic nerve abrogated the immunosuppressive effects of central PGE2 on splenic TNF-alpha mRNA levels. Thus the immune effects of central PGE2 on splenic immune function are mediated by the splenic sympathetic nerve. (Abstract shortened by UMI.)