Peripheral and central cyclooxygenase (COX) products may contribute to the manifestation of brain-controlled sickness responses during localized inflammation induced by macrophage-activating lipopeptide-2 (MALP-2).
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 NFkappaB 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 NFkappaB-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 NFkappaB-activation could be observed in the brains of these animals. We demonstrated that the activation of the brain STAT3 (NFkappaB)-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.
Knorr
Carolin
C
Department of Veterinary-Physiology, Justus-Liebig-University Giessen, Frankfurter Strasse 100, D-35392 Giessen, Germany.
Marks
Doreen
D
Gerstberger
Rüdiger
R
Mühlradt
Peter F
PF
Roth
Joachim
J
Rummel
Christoph
C
D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000502:physiology*; D015232:Dinoprostone / Q000096:biosynthesis; D004326:Drinking; D004435:Eating; D004790:Enzyme Induction; D005334:Fever / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D055666:Lipopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D009043:Motor Activity; D016328:NF-kappa B / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000096:biosynthesis
D055666:Lipopeptides; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; C106335:macrophage stimulatory lipopeptide 2; D051546:Cyclooxygenase 2; D015232:Dinoprostone