PACAP inhibit the release and cytokine activity of HMGB1 and improve the survival during lethal endotoxemia

International Immunopharmacology
Yiting TangXiaoxia Zuo

Abstract

The pathogenesis of sepsis is mediated in part by bacterial endotoxin (lipopolysaccharide; LPS), which stimulates macrophages/monocytes to sequentially release early (e.g., TNF-alpha, IL-1beta) and late [e.g., high mobility group box 1 (HMGB1) protein] pro-inflammatory cytokines. Specifically targeting early mediators has not been effective clinically, in part, because peak mediator activity often has passed before therapy can be initiated. Recent discovery of HMGB1 as a late mediator of lethal sepsis has provided a new target for the treatment of septic shock. Here, we demonstrate that pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide, significantly attenuated circulating HMGB1 levels and increased survival in animals with established endotoxemia, even if treatment began after acute cytokine response has occurred. In vitro, PACAP suppressed LPS-induced HMGB1 release from macrophages/monocytes, even when given 2-4 h after LPS stimulation. PACAP also suppressed HMGB1 release induced by TNF-alpha or IFN-gamma. Moreover, PACAP inhibits HMGB1-induced cytokine release in vitro and in vivo. These results indicate that PACAP inhibits the release and pro-inflammatory activity of HMGB1 and improves s...Continue Reading

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Nov 5, 2008·Expert Reviews in Molecular Medicine·Haichao WangAndrew E Sama
Apr 1, 2009·Shock·Haichao WangAndrew E Sama
Nov 17, 2012·World Journal of Gastroenterology : WJG·Lu-Wen WangZuo-Jiong Gong
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Nov 1, 2016·Reproduction : the Official Journal of the Society for the Study of Fertility·Mathieu Nadeau-ValléeSylvie Girard
Feb 14, 2014·American Journal of Physiology. Renal Physiology·Hailin ZhaoDaqing Ma

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