Pyrexia, anorexia, adipsia, and depressed motor activity in rats during systemic inflammation induced by the Toll-like receptors-2 and -6 agonists MALP-2 and FSL-1

1 Institut für Veterinär-Physiologie, Justus-Liebig-Universität Giessen, Giessen; and 2 Wound Healing Research Group, BioTec Gründerzentrum, Braunschweig, Germany Submitted 9 August 2005 ; accepted in final form 7 September 2005 Macrophage-activating lipopeptide-2 (MALP-2) from Mycoplasma fermentans has been identified as a pathogen-associated molecular pattern of Mycoplasmas that causes activation of the innate immune system through the activation of the heterodimeric Toll-like receptors (TLRs)-2 and -6. The aim of this study was to characterize the ability of MALP-2 and a synthetic analog fibroblast-stimulating lipopeptide-1 (FSL-1; represents the NH 2 -terminal sequence of a lipoprotein from M. salivarium ) to act as exogenous pyrogens, to induce formation of cytokines (endogenous pyrogens), and to cause sickness behavior, such as depressed motor activity, anorexia, and adipsia. For this purpose, body temperature, activity, food intake, and water intake were recorded for 3 days by use of telemetry devices in several groups of rats treated with MALP-2/FSL-1 or the respective control solutions. Intraperitoneal injections of FSL-1 caused fever at doses of 10 or 100 µg/kg, which was preceded by a pronounced phase of hypothermia in response to a dose of 1,000 µg/kg. The maximal fever (a peak of 1.5°C above baseline) was caused by the 100 µg/kg dose with almost identical responses to both MALP-2 and FSL-1. Fever was accompanied by pronounced rises of the proinflammatory cytokines TNF and IL-6 in plasma. Treatment with the TLR-2 and -6 agonists further induced a dose-dependent manifestation of anorexia and adipsia, as well as a reduction of motor activity. We could thus demonstrate that activation of TLR-2 and -6 can induce systemic inflammation in rats accompanied by the classical signs of brain-controlled illness responses. fever; Mycoplasma infection; diacylated mycoplasmal lipopeptides; immune response; proinflammatory cytokines Address for reprint requests and other correspondence: T. Hübschle, Institut für Veterinär-Physiologie, Justus-Liebig-Universität Giessen, Frankfurter Strasse 100, D-35392 Giessen, Germany (e-mail: Thomas.Huebschle{at}vetmed.uni-giessen.de )