Exendin-4 inhibits HMGB1-induced inflammatory responses in HUVECs and in murine polymicrobial sepsis.
Exendin-4 (EX4) has been reported to attenuate myocardial ischemia and reperfusion (I/R) injury and inflammatory and oxidative responses. Nuclear DNA-binding protein high-mobility group box 1 (HMGB1) protein acts as a late mediator of severe vascular inflammatory conditions. However, the effect of EX4 on HMGB1-induced inflammatory response has not been studied. First, we accessed this question by monitoring the effects of posttreatment EX4 on lipopolysaccharide (LPS) and cecal ligation and puncture (CLP)-mediated release of HMGB1 and HMGB1-mediated regulation of proinflammatory responses in human umbilical vein endothelial cells (HUVECs) and septic mice. Posttreatment EX4 was found to suppress LPS-mediated release of HMGB1 and inhibited HMGB1-mediated hyperpermeability and leukocyte migration in septic mice. EX4 also induced downregulation of CLP-induced release of HMGB1, production of IL-6, and mortality. Collectively, these results suggest that EX4 may be regarded as a candidate therapeutic agent for treatment of vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway.
College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, 702-701, Republic of Korea.
Wonhwa
W
Lee
Sae-Kwang
SK
Ku
Eun Ji
EJ
Park
Dong Hee
DH
Na
Kyung-Min
KM
Kim
Jong-Sup
JS
Bae
D000818:Animals; D060085:Coinfection / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*
D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D010455:Peptides; D014688:Venoms; D000077270:Exenatide