PACAP inhibit the release and cytokine activity of HMGB1 and improve the survival during lethal endotoxemia.
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 survival during lethal endotoxemia, which confirms this peptide as a candidate for therapy of septic shock.
Tang
Yiting
Y
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan 410078, PR China. victor443@sina.com.cn
Lv
Ben
B
Wang
Haichao
H
Xiao
Xianzhong
X
Zuo
Xiaoxia
X
D000818:Animals; D002478:Cells, Cultured; D019446:Endotoxemia / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D008807:Mice, Inbred BALB C; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D024243:HMGB1 Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma