GRAM-NEGATIVE AND GRAM-POSITIVE BACTERIAL PRODUCTS INDUCE DIFFERENTIAL CYTOKINE PROFILES IN THE BRAIN - ANALYSIS USING AN INTEGRATIVE MOLECULAR-BEHAVIORAL IN-VIVO MODEL

Bacterial-derived products [e.g., lipopolysaccharide (LPS) from Gram-n egative and muramyl dipeptide (MDP) from Gram-positive bacteria] are p roposed to play a pivotal role in the generation of neurological and n euro-inflammatory/ immunological responses during bacterial infections of the nervous system. LPS and MDP may act through cytokines; cytokin e-neuropeptide interactions may also be involved. Here, we investigate d cytokine and neuropeptide mRNA profiles in specific brain regions in response to the intracerebroventricular administration of LPS and MDP . IL-1 beta system components (ligand, signalling receptor, receptor a ccessory proteins, receptor antagonist), TNF-alpha, TGF-beta 1, glycop rotein 130 (IL-6 receptor signal transducer), OB protein (leptin) rece ptor, neuropeptide Y, Y5 receptor, and pro-opiomelanocortin (opioid pe ptide precursor) mRNAs were analyzed. The same brain region sample was assayed for all components. LPS and MDP administration induced signif icantly different behavioral and molecular profiles. LPS was significa ntly more potent than MDP in inducing anorexia and in up-regulating pr o-inflammatory cytokines (IL-1 beta and TNF-alpha) mRNAs in the cerebe llum, hippocampus and hypothalamus; MDP was more potent in up-regulati ng antiinflammatory cytokine (IL-1 receptor antagonist and TGF-beta 1) mRNAs. LPS and MDP also modulated hypothalamic IL-1 receptor mRNA com ponents, but did not affect any of the neuropeptide-related components examined. The results suggest that the magnitude of neurological mani festations induced by LPS and MDP may involve the ratio between stimul atory and inhibitory cytokines, and this ratio may have implications f or the neuroinflammatory/neurotoxic events associated with bacterial i nfections of the central nervous system.