Background: 

Rats systemically treated with the diacylated lipopeptide macrophage-activating lipopeptide-2 (MALP-2) show brain-controlled acute-phase response symptoms such as fever, anorexia, adipsia, and depressed motor activity. These responses are most likely mediated via activation of Toll-like receptors (TLRs) -2 and -6 and the subsequent induction of proinflammatory cytokines including tumor necrosis factor a (TNF) and interleukin-6 (IL-6). Brain-controlled sickness responses can also be induced by a localized inflammatory response caused by MALP-2 injections into a subcutaneous air pouch, with just small amounts of IL-6 (and no TNF) present in the systemic circulation. Here we investigated whether an inflammatory activation of the brain can be demonstrated in response to systemic intraperitoneal or local intra-pouch injections of MALP-2, and whether local (peripheral) or central cyclooxygenase (COX)-2-dependent formations of prostaglandin E2 (PGE2) are involved in MALP-2-induced illness responses.

Methods: 

Rats 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. Local (intra-pouch) and circulating levels of PGE2 were measured by use of an ELISA. Inflammatory activation of the brain in response to systemic or local stimulation with MALP-2 was determined by the immunohistochemical detection of a nuclear translocation of the transcription factors NFkB (nuclear factor kB) and STAT3 as well as the appearance of COX-2 in brain areas relevant for the induction of centrally controlled signs of illness.

Results: 

Local (intra-pouch) treatment with the preferential COX-2 inhibitor meloxicam attenuated, but not abolished fever and some of the other illness responses induced by local injections of MALP-2 into the pouch. Local MALP-2-induced formation of PGE2 was blunted and plasma PGE2 levels were reduced by treatment with meloxicam. In the brain, systemic stimulation with MALP-2 induced nuclear STAT3- and NFkB-translocation in the brain vasculature and the sensory circumventricular organs, which was accompanied by a prominent increase in COX-2 immunreactivity (IR) in endothelial cells. Local MALP2-treatment induced a moderate STAT3-activation and a small but significant increase in COX2-IR while almost no NFkB-activation could be observed in the brains of these animals.

Conclusions: 

We were able to demonstrate that the activation of the brain STAT3(NFkB)-COX2 singling cascade seems to be involved in the manifestation of brain controlled illness symptoms induced by systemic and local inflammatory stimulation with MALP-2. In addition, the present data as well suggest a small but significant contribution of locally (peripheral) produced PGE2 to MALP-2-induced activation of brain controlled sickness responses like fever.