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1 Veterinary-Physiology, Justus-Liebig-University Giessen, Giessen, Germany
2 Wound Healing Research Group, BioTec Gruenderzentrum, Braunschweig, Germany
* To whom correspondence should be addressed. E-mail: Thomas.Huebschle{at}vetmed.uni-giessen.de.
Macrophage-activating lipopeptide 2 (MALP-2) from Mycoplasma fermentans has been identified as a pathogen-associated molecular pattern of mycoplasmas, which causes activation of the innate immune system through the activation of the heterodimeric Toll-like receptors (TLRs) 2 and 6. Aim of the study was to characterize the ability of MALP-2 and a synthetic analogue fibroblast-stimulating lipopeptide 1 (FSL-1, represents the N-terminal sequence of a lipoprotein from Mycoplasma salivarium) to act as exogenous pyrogens, to induce formation of cytokines (endogenous pyrogens), and to cause sickness behaviour such as depressed motor activity, anorexia and adipsia. For this purpose, body temperature, activity, food intake, and water intake were recorded for three 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 1000 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 tumor necrosis factor and interleukin-6 in plasma. Treatment with the TLR2/6 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 TLR2/6 can induce systemic inflammation in rats, which is accompanied by the classical signs of brain-controlled illness responses.
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