Differential sensitivities of pyrogenic chemokine fevers to cyclooxygenase isozymes antibodies.
It has been proposed that prostaglandin (PG)E(2) production via a process catalyzed by the inducible isoform of cyclooxygenase (COX)-2 and activation of specific PGE(2) receptor subtypes within the preoptic/anterior hypothalamus (AH/POA) is the last step and unique pathway in the induction of a fever. However, many data support the existence of a PG-independent pathway. That is, other more rapid mechanisms, which involve the constitutive COX-1 isozyme, may be more critical for a PG-dependent fever. Thus, we examined the role of both COX isoforms in the AH/POA in fevers induced by macrophage inflammatory protein (MIP)-1beta, a PG-independent pyrogen, and RANTES (regulated on activation, normal T-cells expressed and secreted), a PG-dependent pyrogen. In freely moving rats, two independent polyclonal antibodies were used which neutralize COX-1 and COX-2. The microinjection of either MIP-1beta or RANTES into the pyrogen-sensitive region of the AH/POA induced an intense fever of rapid onset. Peripheral pretreatment with an antipyretic dose of dexamethasone which prevents COX-2 expression, or the microinjections into the AH/POA of either anti-COX-1 or anti-COX-2, blocked the febrile response induced by RANTES but not that induced by MIP-1beta. These results provide strong evidence for the existence of rapid mechanisms in the AH/POA which involve both COX isozymes during the fever induced by RANTES, and further support the existence of an alternative PG-independent pathway in the febrile response.
Tavares
Eva
E
Valme Hospital Research Unit, Division of Experimental and Clinical Pharmacology, Seville, Spain.
Miñano
Francisco J
FJ
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000008:administration & dosage / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D005334:Fever / Q000139:chemically induced*; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008845:Microinjections; D011301:Preoptic Area / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000276:immunology; D011749:Pyrogens / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000906:Antibodies; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D007527:Isoenzymes; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D011749:Pyrogens; D003907:Dexamethasone; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D015232:Dinoprostone