Selective contribution of interleukin-6 and leptin to brain inflammatory signals induced by systemic LPS injection in mice.
This study aimed to address the relative contributions of the proinflammatory cytokine interleukin-6 (IL-6) and the cytokine-like hormone leptin to the genomic activation of brain cells during lipopolysaccharide (LPS)-induced systemic inflammation. Wildtype and IL-6KO mice were injected with LPS (50 microg/kg, intraperitoneally) and the brains analyzed by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR). LPS induced a pronounced nuclear translocation of the signal transducer and activator of transcription (STAT3) throughout the brains of wildtype mice, an effect that was significantly diminished, but not abolished, in the IL-6KOs. The remnant STAT3-activation, although still observed within some of the same areas activated by IL-6, was most intense in ependymal and meningial cells and along distinct blood vessels throughout the brain. This expression was almost totally abolished in the presence of an anti-leptin antiserum. Interestingly, the induction of cyclooxygenase 2 and microsomal prostaglandin E synthase (mPGES), the rate-limiting enzymes for synthesis of PGE2 by LPS, was diminished to a degree that correlated with the absence of IL-6 but not entirely with leptin. These results demonstrate that the induction of the inflammatory pathway in the brain is mediated by both IL-6 and leptin, which appear to work in tandem. Unlike IL-6, however, the contribution of leptin to this response was limited to distinct cell types/brain areas and STAT3-responsive target genes implicated in the brain-controlled sickness-type response. The physiological significance of leptin's action on meningeal and endothelial cells remains to be clarified but might reflect a role in LPS-induced immune cell infiltration into the brain.
Rummel
Christoph
C
Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, H4H 1R3, Canada. Christoph.D.Rummel@vetmed.uni-giessen.de
Inoue
Wataru
W
Sachot
Christelle
C
Poole
Stephen
S
Hübschle
Thomas
T
Luheshi
Giamal N
GN
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000276:immunology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D020738:Leptin / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072000:NF-KappaB Inhibitor alpha; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D020672:I-kappa B Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D020738:Leptin; D008070:Lipopolysaccharides; C000606205:Nfkbia protein, mouse; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014841:von Willebrand Factor; D000072000:NF-KappaB Inhibitor alpha; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases