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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 μg/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. J. Comp. Neurol. 511:373–395, 2008. © 2008 Wiley‐Liss, Inc.