Hypoxia/reoxygenation-induced HMGB1 translocation and release promotes islet proinflammatory cytokine production and early islet graft failure through TLRs signaling.

Autor: Cheng Y; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China; Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China., Xiong J; Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, P.R. China., Chen Q; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China., Xia J; Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Chongqing Medical University, Chongqing 400016, P.R. China., Zhang Y; Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, P.R. China., Yang X; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China., Tao K; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China., Zhang S; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China., He S; Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing 400016, P.R. China. Electronic address: hesirong@cqmu.edu.cn.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular basis of disease [Biochim Biophys Acta Mol Basis Dis] 2017 Feb; Vol. 1863 (2), pp. 354-364. Date of Electronic Publication: 2016 Nov 10.
DOI: 10.1016/j.bbadis.2016.11.012
Abstrakt: High-mobility group box 1 (HMGB1) translocation and release, which is involved in several tissue types of ischemia-reperfusion injuries, activate innate immunity by inducing proinflammatory cytokine production through its interaction with toll-like receptors (TLRs). Our objective was to determine the role of HMGB1 and the degree of activation of TLR-related signal transduction pathways in hypoxia/reoxygenation (H/R)-induced proinflammatory cytokine production and intra-islet graft inflammation. After islets are exposed to hypoxia-reoxygenation for 24h, TLR2/4 expression and TLR-mediated signaling was up-regulated in islets, and HMGB1 was translocated from the nucleus to the cytoplasm and released to the extracellular space. With H/R exposure, proinflammatory cytokine production (IL-1β and TNF-α) and islet injury were significantly increased, and these effects depend on TLR2/4 signaling pathways. Exogenous HMGB1 also induces islet inflammation and increases the phosphorylation of STAT3, p38 and IκBα in wild-type islets. TLR2 deficiency in TLR2-KO islets resulted in the inhibition of IL-1β production and STAT3/p38 phosphorylation after HMGB1 exposure. TLR4 deficiency in TLR4-KO islets resulted in the inhibition of TNF-α production and IκBα phosphorylation after HMGB1 exposure. Pre-incubation of the STAT3, p38, or NF-κB inhibitors significantly inhibited HMGB1-induced IL-1β or TNF-α production in islets, but the effect of HMGB1 or H/R-induced islet injury was not counteracted by a separate treatment of the STAT3 inhibitor, p38 inhibitor, or NF-κB inhibitors. HMGB1 inhibition by ethyl pyruvate or blockade by neutralizing antibodies significantly decreased the phosphorylation of STAT3, p38 and IκBα, the production of IL-1β and TNF-α, and the islet injury in wild-type islets after exposure to H/R and significantly improved early islet graft failure. Thus, our results suggest that HMGB1 released from H/R induced islets works in an autocrine manner to up-regulate STAT or p38 and augment IL-1β production via TLR2, and up-regulate NF-κB and augment TNF-α production via TLR4 in intra-islet, which are associated with H/R-induced islet injury and early graft failure.
(Copyright © 2016 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: