title: Overactivation of mitogen-activated protein kinase and suppression of mitofusin-2 expression are two independent events in high mobility group box 1 protein-mediated T cell immune dysfunction.
abstract: High mobility group box 1 protein (HMGB1), a critical proinflammatory cytokine, has recently been identified to be an immunostimulatory signal involved in sepsis-related immune dysfunction when released extracellularly, but the potential mechanism involved remains elusive. Here, we showed that the treatment with HMGB1 in vitro inhibited T lymphocyte immune response and expression of mitofusin-2 (Mfn-2; a member of the mitofusin family) in a dose- and time-dependent manner. Upregulation of Mfn-2 expression attenuated the suppressive effect of HMGB1 on T cell immune function. The phosphorylation of both extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) was markedly upregulated by treating with high amount of HMGB1, while pretreatment with ERK1/2 and p38 MAPK-specific inhibitors (U0126 and SB203580) could attenuate suppression of T cell immune function and nuclear factor of activated T cell (NFAT) activation induced by HMGB1, respectively. HMGB1-induced activity of ERK1/2 and p38 was not fully inhibited in the presence of U0126 or SB203580. Interestingly, overexpression of Mfn-2 had no marked effect on HMGB1-mediated activation of MAPK, but could attenuate the suppressive effect of HMGB1 on the activity of NFAT. Thus, the mechanisms involved in HMGB1-induced T cell immune dysfunction in vitro at least partly include suppression of Mfn-2 expression, overactivation of ERK1/2, p38 MAPK, and intervention of NFAT activation, while the protective effect of Mfn-2 on T cell immune dysfunction induced by HMGB1 is dependent on other signaling pathway associated with NFAT, but not MAPK. Taken together, we conclude that overactivation of MAPK and suppression of Mfn-2 expression are two independent events in HMGB1-mediated T cell immune dysfunction.
authors.affiliation: Emergency Department, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, P. R. China. lzq640815@163.com
authors.forename: Zhong-qiu
authors.initials: ZQ
authors.lastname: Lu
authors.forename: Lu-ming
authors.initials: LM
authors.lastname: Tang
authors.forename: Guang-ju
authors.initials: GJ
authors.lastname: Zhao
authors.forename: Yong-ming
authors.initials: YM
authors.lastname: Yao
authors.forename: Xiao-mei
authors.initials: XM
authors.lastname: Zhu
authors.forename: Ning
authors.initials: N
authors.lastname: Dong
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
mesh_terms: D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D007093:Imidazoles; D024101:Mitochondrial Proteins; D050778:NFATC Transcription Factors; D011725:Pyridines; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C093642:SB 203580