Background: 

Macrophage-activating lipopeptide-2 (MALP-2) from Mycoplasma fermentans seems to induce an innate immune response via activation of Toll-like receptors (TLRs) 2 and 6. CD36 is regarded as a cellular sensor of diacylated lipopetides such as MALP-2 and may be required for the array of MALP-2-induced effects in vivo. We therefore tested the responses of TLR2-knockout mice (TLR2-KO) and wildtype mice (C57-BL6), and of CD36 deficient spontaneously hypertensive rats (SHR) and their genetic controls (Wistar Kyoto rats, WKY) to systemic stimulations with the TLR2/6 agonist MALP-2 and the TLR4 agonist lipopolysaccharide (LPS).

Methods: 

TLR2-KO, C57-BL6, SHR and WKY were intra-abdominally implanted with radiotransmitters for recording of body temperature (fever) and motor activity. Food and water intake were also measured by a telemetric device to determine a possible development of anorexia and adipsia as characteristic components of brain-controlled sickness responses. Circulating levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) were measured by use of specific bioassays. Inflammatory activation of the brain was determined by the quantification of a nuclear translocation of the transcription factor STAT3 (signal transducer and activator of transcription 3) in brain areas, relevant for the manifestation of fever and sickness behavior.

Results: 

Fever and formation of TNF and IL-6 induced by intraperitoneal injections of MALP-2 were completely blunted in TLR2-KO mice, while LPS-induced responses were not impaired in these animals when compared to those of C57-BL6 wildtype mice. In SHR lacking CD36 an attenuation of fever and sickness behavior was observed in response to MALP-2, but even to a higher degree in response to LPS, when compared to WKY controls. Circulating cytokines and numbers of nuclear STAT3 signals in relevant areas of the brain were identical in SHR and WKY after stimulation with both pyrogens, indicating that the inflammatory activation of the brain in response to MALP-2 (and LPS) is not impaired by the lack of CD36.

Conclusions: 

These results demonstrate unequivocally that TLR2 is essential for the manifestation of MALP-2-induced (but not for LPS-induced) inflammatory responses. A moderate participation of CD36 in MALP-2-induced sickness- and cytokine-responses can not be ruled out, but is rather unlikely since LPS-induced inflammatory responses were also attenuated in SHR. The observed attenuations of MALP-2 and LPS-induced fevers in SHR may rather be caused by some of the endocrine abnormalities in these rats resulting in stronger endogenous antipyretic capacities.