Fever and circulating cytokines induced by double-stranded RNA in guinea pigs: dependence on the route of administration and effects of repeated injections.

The aim of this study was to characterize the properties of synthetic double-stranded RNA to induce fever and circulating cytokines in guinea pigs with special emphasis on the route of administration and on a putative development of tolerance to this pyrogen. Changes in abdominal temperature were recorded in unrestrained animals by use of intra-abdominally implanted radiotransmitters. Circulating concentrations of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by use of specific bioassays. The pyrogenic effect of double-stranded RNA at a dose of 500 microg kg(-1) depended on the route of its administration. Intra-arterial (i.a.) or intraperitoneal injections of double-stranded RNA induced pronounced fevers and strong elevations of circulating TNF-alpha and IL-6. Intramuscular injections of the synthetic pyrogen caused rather moderate febrile and cytokine responses. Administration of synthetic RNA into artificial subcutaneously implanted Teflon chambers had no pyrogenic and cytokine-inducing effects. I.a. injections of double-stranded RNA, repeated five times at intervals of 3 days, resulted in fevers of similar shape and duration and similar cytokine response patterns. However, the strength of fever and cytokine formation was significantly reduced, although not abolished, in response to the repeated injections compared with the first injection, indicating a partial development of tolerance. The modulation of the strength of RNA-induced fever, dependent on the route of administration, or the state of partial tolerance to this pyrogen, may thus be related to the formation of pyrogenic cytokines.