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Recently, it has been shown that the Toll-like receptors-2 and -6 agonist fibroblast-stimulating lipopeptide-1 (FSL-1) have the capacity to induce fever and sickness behavior in rats. Since the mechanisms of the fever-inducing effects of FSL-1 are still unknown, we tested the pyrogenic properties of FSL-1 in guinea pigs and assessed a role for TNF-alpha and prostaglandins in the manifestation of the febrile response to this substance. Intra-arterial and intraperitoneal injections of FSL-1 caused dose-dependent fevers that coincided with elevated plasma levels of TNF and IL-6, the intraperitoneal route of administration being more effective than the intra-arterial route. Intra-arterial or intraperitoneal injection of a soluble form of the TNF type 1 receptor, referred to as TNF binding protein (TNFbp), together with FSL-1, completely neutralized FSL-1-induced circulating TNF and reduced fever and circulating IL-6. Intra-arterial or intraperitoneal injection of the nonselective cyclooxygenase (COX)-inhibitor diclofenac depressed fever and FSL-1-induced elevations of circulating PGE2. Circulating TNF and IL-6, however, remained unimpaired by treatment with diclofenac. In conclusion, FSL-1-induced fever in guinea pigs depends, in shape and duration, on the route of administration and is, to a high degree, mediated by pyrogenic cytokines and COX products.