Abstract
We investigated whether an inflammation-dependent activation of the brain occurs in response to systemic intraperitoneal (i.p.) or local injections of macrophage-activating lipopeptide-2 (MALP-2) into a subcutaneous (s.c.) air pouch, and whether local (peripheral) or central cyclooxygenase (COX)-2-dependent formations of prostaglandin E 2 (PGE 2) are involved in MALP-2-induced illness responses. Body temperature, activity, food and water intake were measured telemetrically. Local (s.c.) and circulating levels of PGE 2 were measured by an ELISA. Inflammatory activation of the brain in response to MALP-2 was determined by immunohistochemical detection of the transcription factors NFκB and STAT3 in cell nuclei as well as the appearance of COX-2 at the same sites. S.c. treatment with the preferential COX-2 inhibitor meloxicam attenuated, but not abolished fever induced by local injections of MALP-2 into the pouch. Local MALP-2-induced formation of PGE 2 was blunted by treatment with meloxicam. In the brain, i.p. stimulation with MALP-2-induced nuclear STAT3- and NFκB-translocation in the vasculature and the sensory circumventricular organs, which was accompanied by an increase in COX-2 immunoreactivity (IR) in endothelial cells. Local MALP-2-treatment induced a moderate STAT3 activation and a small but significant increase in COX-2 IR while no NFκB-activation could be observed in the brains of these animals. We demonstrated that the activation of the brain STAT3 (NFκB)-COX-2 singling cascade seems to be involved in the manifestation of brain-controlled illness symptoms induced by systemic and local inflammatory stimulation with MALP-2. The present data further suggest a contribution of peripherally produced PGE 2 to MALP-2-induced activation of brain sites implicated in fever.
Published Version
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