Modulation of the prostaglandin responses of conscious rabbits to the pyrogen polyinosinic:polycytidylic acid by corticotrophin-releasing factor-41.
The pyrogenic interferon inducer polyinosinic:polycytidylic acid (Poly I:C) was shown to stimulate rises in both prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) in conscious rabbits in vivo. Poly I:C (2.5 micrograms/kg) stimulated a fivefold rise in circulating immunoreactive (ir) PGE2, with a lag phase of 60 min, which was sustained during the subsequent 4-h period of observation. Poly I:C also stimulated a 2.5-fold rise in circulating irPGF2 alpha with a lag phase of 90 min, which was followed by a return to basal levels after 5 h. The rises in circulating irPGE2 and irPGF2 alpha stimulated by Poly I:C were prevented by pretreatment with the non-steroidal anti-inflammatory drug ketoprofen. Both the irPGE2 and irPGF2 alpha responses to Poly I:C (2.5 micrograms/kg, i.v.) were antagonized by the corticotrophin-releasing factor-41 (CRF-41) receptor antagonist (alpha-helical CRF (9-41), 25 micrograms/kg, i.v.) administered 5 min prior to the pyrogen. Peripheral immunoneutralization using an anti-CRF-41 monoclonal antibody (KCHMB001, 2.5 mg/kg, i.v.) administered 5 min prior to the pyrogen, also inhibited both the PGE2 and PGF2 alpha responses to Poly I:C (2.5 micrograms/kg, i.v.). However, control mouse IgG also inhibited the PGE2 response. In conclusion, these results suggest a modulatory role for endogenous peripheral CRF-41 in the circulating prostaglandin responses to the pyrogen Poly I:C and this effect may be responsible for the antipyretic actions of peripherally administered CRF-41 antagonists and antibodies.
Department of Clinical Biochemistry, University of Newcastle upon Tyne, U.K.
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Milton
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Hillhouse
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Milton
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology / Q000502:physiology*; D015237:Dinoprost / Q000097:blood; D015232:Dinoprostone / Q000097:blood; D007660:Ketoprofen / Q000494:pharmacology; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology*; D011453:Prostaglandins / Q000097:blood*; D011817:Rabbits; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D013696:Temperature; D013997:Time Factors
D000911:Antibodies, Monoclonal; D010446:Peptide Fragments; D011453:Prostaglandins; D018019:Receptors, Corticotropin-Releasing Hormone; D003346:Corticotropin-Releasing Hormone; D007660:Ketoprofen; C045089:corticotropin releasing hormone (9-41); D015237:Dinoprost; D015232:Dinoprostone; D011070:Poly I-C