Fever and inflammatory cytokine response in rats injected subcutaneously with viral double-stranded RNA analog, polyinosinic:polycytidylic acid (Poly-I:C)

The objective of this study was to determine whether viral double-stranded RNA analog, polyinosinic:polycytidylic acid (Poly-I:C), is pyrogenic in rats when administered subcutaneously, thus determining whether rats can serve as an experimental model to investigate the regulation of local and systemic inflammatory responses to a Toll-like receptor(TLR)-3 agonist. Rats implanted intraperitoneally with temperature-sensitive radiotelemeters were injected subcutaneously in the skin of the tail with saline, 100 μg kg−1 Poly-I:C, or 1000 μg kg−1 Poly-I:C. In a separate group of rats blood and tail-skin samples were taken 3 and 24 h after injections to assess changes in local and systemic inflammatory cytokine release. Injection of 1000 μg kg−1 Poly-I:C induced an acute fever, which lasted for approximately seven hours. The fever was associated with elevated local tissue concentrations of interleukin(IL)-1β, IL-6, and cytokine-induced neutrophil chemoattractant (CINC)-1, and elevated plasma concentration of CINC-1. Cytokine concentrations had returned to background concentrations by 24 h after the injection. Injection of 100 μg kg−1 Poly-I:C failed to induce fever, but did induce significant increases in the local tissue, but not circulating, concentration of CINC-1 within 3 h of the injection. Tissue CINC-1 concentrations had returned to background concentrations by 24 h after the injection. In conclusion, when administered at great enough concentrations, subcutaneously injected Poly-I:C is pyretic in rats, and the pyresis is associated with elevated concentrations of local and systemic inflammatory mediators. Thus the rat can be used to study signaling pathways induced by localized, subcutaneous administration of this TLR-3 agonist that mimics viral infection.

► Subcutaneous injection of TLR-3 agonist Poly-I:C is pyrogenic in rats.
► Subcutaneous Poly-I:C induces increases in local and circulating cytokines.
► Poly-I:C-induced chemokine CINC-1 (CXCL1) may be a novel mediator of fever