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-negative and muramyl dipeptide (MDP) from Gram-positive bacteria] are proposed to play a pivotal role in the generation of neurological and neuroinflammatory/immunological responses during bacterial infections of the nervous system. LPS and MDP may act through cytokines; cytokine-neuropeptide interactions may also be involved. Here, we investigated cytokine and neuropeptide mRNA profiles in specific brain regions in response to the intracerebroventricular administration of LPS and MDP. IL-beta1 system components (ligand, signalling receptor, receptor accessory proteins, receptor antagonist), TNF-alpha, TGF-beta1, glycoprotein 130 (IL-6 receptor signal transducer), OB protein (leptin) receptor, neuropeptide Y, Y5 receptor, and pro-opiomelanocortin (opioid peptide precursor) mRNAs were analyzed. The same brain region sample was assayed for all components. LPS and MDP administration induced significantly different behavioral and molecular profiles. LPS was significantly more potent than MDP in inducing anorexia and in up-regulating pro-inflammatory cytokines (IL- beta1 and TNF-alpha mRNAs in the cerebellum, hippocampus and hypothalamus; MDP was more potent in up-regulating anti-inflammatory cytokine (IL-1 receptor antagonist and TGF-beta1) mRNAs. LPS and MDP also modulated hypothalamic IL-1 receptor mRNA components, but did not affect any of the neuropeptide-related components examined. The results suggest that the magnitude of neurological manifestations induced by LPS and MDP may involve the ratio between stimulatory and inhibitory cytokines, and this ratio may have implications for the neuroinflammatory/neurotoxic events associated with bacterial infections of the central nervous system.
Plata-Salamán
C R
CR
Division of Molecular Biology, School of Life and Health Sciences, University of Delaware, Newark, Delaware 19716-2590, USA.
Ilyin
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SE
Gayle
D
D
Flynn
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MC
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics; D001921:Brain / Q000276:immunology* / Q000382:microbiology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D004435:Eating; D006090:Gram-Negative Bacteria / Q000276:immunology; D006094:Gram-Positive Bacteria / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000235:genetics; D053577:Interleukin-1 Receptor Accessory Protein; D008070:Lipopolysaccharides / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D054411:Receptors, Leptin; D017476:Receptors, Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
D015703:Antigens, CD; D002352:Carrier Proteins; D016207:Cytokines; C507766:Il1rap protein, rat; C494201:Il6st protein, rat; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D053577:Interleukin-1 Receptor Accessory Protein; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009478:Neuropeptide Y; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017472:Receptors, Interleukin-1; D054411:Receptors, Leptin; D017476:Receptors, Neuropeptide Y; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C100568:neuropeptide Y5 receptor; D050822:Cytokine Receptor gp130; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D011333:Pro-Opiomelanocortin