Cytokines, but not corticotropin-releasing factor and endothelin-1, participate centrally in the febrile response in zymosan-induced arthritis in rats

• Centrally acting endogenous pyrogens mediate fever in zymosan-induced arthritis.
• Fever in zymosan-induced arthritis depends on central effects of cytokines.
• Fever in zymosan-induced arthritis does not depend on CRF and ET-1.

Recent literature has revealed that centrally generated prostaglandins participate in the febrile response in zymosan-induced arthritis in rats. However, it is not clear whether other centrally acting pyrogenic mediators such as cytokines, endothelins (ETs), and the corticotropin-releasing factor (CRF) contribute to the febrile response in this model. In the present study, rats were pretreated with intracerebroventricular (i.c.v.) injections of soluble TNF receptor I (sTNFRI), recombinant IL-1 receptor antagonist (IL-1ra), anti-rat IL-6 monoclonal antibody (AbIL-6), α-helical CRF9–41 (a nonselective CRF1/CRF2 receptor antagonist), BQ-123 (an ETA receptor antagonist), BQ-788 (an ETB receptor antagonist), and artificial cerebrospinal fluid (aCSF, control) prior to an intra-articular zymosan (4 mg) injection. Rectal temperatures were measured with a telethermometer. The administration of IL-1ra (200 µg), sTNFRI (500 ng), and AbIL-6 (5 µg) attenuated body temperature elevations after a zymosan injection. The administration of BQ-788 (3 pmol), BQ-123 (3 pmol), and α-helical CRF9-41 (25 µg) did not affect the zymosan-induced febrile response. All the compounds used to pretreat the animals did not significantly alter their basal body temperatures. Together, the results here demonstrate that the febrile response in zymosan-induced arthritis in rats depends on the centrally acting pyrogenic cytokines TNF-α, IL-1β, and IL-6, but does not depend on either CRF or ET-1.