O037 Differential roles for IL-23 and IL-17 in inflammatory bowel disease

Towne, JE; Maxwell, Joe; Zhang, Y.; Brown, W. A.; Rottman, James B.; Budelsky, Alison

doi:10.1016/j.cyto.2012.06.074

Cited by 3 publications

(1 citation statement)

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“…IL-17A is a pro-inflammatory cytokine involved in the initiation and maintenance of several autoimmune disorders such as encephalomyelitis and inflammatory bowel disease 17 29 . One of the most important mechanistic attributes of IL-17A in this context is its modulation of the tight junction protein organization in endothelial cells, which thereby promotes blood-brain barrier disruption and central nervous system inflammation 30 31 .…”

Section: Discussionmentioning

confidence: 99%

Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization

Meng

Banerjee

et al. 2015

Sci Rep

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Sepsis is the predominant cause of mortality in ICUs, and opioids are the preferred analgesic in this setting. However, the role of opioids in sepsis progression has not been well characterized. The present study demonstrated that morphine alone altered the gut microbiome and selectively induced the translocation of Gram-positive gut bacteria in mice. Using a murine model of poly-microbial sepsis, we further demonstrated that morphine treatment led to predominantly Gram-positive bacterial dissemination. Activation of TLR2 by disseminated Gram-positive bacteria induced sustained up-regulation of IL-17A and IL-6. We subsequently showed that overexpression of IL-17A compromised intestinal epithelial barrier function, sustained bacterial dissemination and elevated systemic inflammation. IL-17A neutralization protected barrier integrity and improved survival in morphine-treated animals. We further demonstrated that TLR2 expressed on both dendritic cells and T cells play essential roles in IL-17A production. Additionally, intestinal sections from sepsis patients on opioids exhibit similar disruption in gut epithelial integrity, thus establishing the clinical relevance of this study. This is the first study to provide a mechanistic insight into the opioid exacerbation of sepsis and show that neutralization of IL-17A might be an effective therapeutic strategy to manage Gram-positive sepsis in patients on an opioid regimen.

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