Influence of systemic treatment with cyclooxygenase inhibitors on lipopolysaccharide-induced fever and circulating levels of cytokines and cortisol in guinea-pigs.
Peripheral inflammatory stimuli result in the modification of a number of vital brain-controlled functions including the thermoregulatory set-point (induction of fever) and the activity of the hypothalamic-pituitary-adrenal (HPA) axis. We addressed the question of whether both of these components of the acute-phase response are induced by a common signal pathway. For this purpose we recorded body temperature (by remote radio-telemetry), HPA axis activity (circulating concentrations of cortisol by radio-immunoassay) and levels of the pro-inflammatory cytokines tumour necrosis factor and interleukin-6 (TNF, IL-6, using specific bioassays) in six groups of guinea-pigs. The animals received intra-arterial injections of either 10 microg/kg lipopolysaccharide (LPS) plus saline, 10 microg/kg LPS plus 5 mg/kg meloxicam (an inhibitor of the inducible form of cyclooxygenase), 10 microg/kg LPS plus 5 mg/kg diclofenac (a non-selective cyclooxygenase inhibitor), saline plus solvent, saline plus 5 mg/kg meloxicam or saline plus 5 mg/kg diclofenac. Injection of the cyclooxygenase inhibitors per se had no influence on the investigated parameters. Injection of LPS alone resulted in a biphasic fever, a more than fivefold increase in circulating cortisol and pronounced induction of TNF and IL-6. Treatment with the cyclooxygenase inhibitors either attenuated (meloxicam) or abolished (diclofenac) LPS-induced fever, but had no effect on the LPS-induced rise of plasma cortisol or IL-6. Circulating levels of TNF, in response to LPS, were enhanced by meloxicam and diclofenac, reflecting the negative feedback control exerted by prostaglandins on cytokine (specifically TNF) formation. These results provide the first evidence that the prostaglandin-dependent inflammatory pathway for fever induction is distinct from the pathway of HPA axis activation since fever, but not circulating cortisol, was attenuated by an inhibition of prostaglandin formation.
Roth
Joachim
J
Institut für Veterinär-Physiologie, Justus-Liebig-Universität, Frankfurter Strasse 100, 35392 Giessen, Germany. joachim.roth@vetmed.uni-giessen.de
Hübschle
Thomas
T
Pehl
Ulrich
U
Ross
Günter
G
Gerstberger
Rüdiger
R
D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology; D005334:Fever / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D006168:Guinea Pigs; D006854:Hydrocortisone / Q000097:blood*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000097:blood*; D008070:Lipopolysaccharides; D008297:Male; D000077239:Meloxicam; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000276:immunology; D011453:Prostaglandins / Q000502:physiology; D013686:Telemetry; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011453:Prostaglandins; D013843:Thiazines; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D000077239:Meloxicam; D006854:Hydrocortisone