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TIFA upregulation after hypoxia-reoxygenation is TLR4- and MyD88-dependent and associated with HMGB1 upregulation and release.

Abstract
TRAF-interacting protein with a forkhead-associated domain (TIFA) is a tumor necrosis factor receptor-associated factor 6 (TRAF6) binding protein that mediates IL-1 signaling. We recently reported that TIFA mRNA is significantly upregulated early in the liver after trauma and hemorrhagic shock. In this study, we sought to characterize the upregulation of TIFA by hypoxia-reoxygenation and investigate its role in hypoxia-induced signaling. TIFA expression was detected by qRT-PCR and Western blotting in both mouse hemorrhagic shock with resuscitation (HS-R) and hepatocytes exposed to hypoxia-reoxygenation. Involvement of TLR4 and MyD88 was assessed using cells from TLR4(-/-) and MyD88(-/-) mice. The interaction of TIFA with TRAF6 and IRAK-1 was investigated using coimmunoprecipitation in vitro. RNAi was performed to knock down the endogenous expression of the TIFA gene in hepatocytes. High-mobility-group box 1 protein (HMGB1) expression was detected by Western blotting and ELISA, and the activation of NF-κB and MAPK was measured with EMSA and Western blotting. The results showed that TIFA expression was upregulated after HS-R in vivo and hypoxia-reoxygenation in vitro. Further analysis revealed that hypoxia-reoxygenation-induced upregulation of TIFA was TLR4- and MyD88-dependent. Moreover, TIFA was found to associate with TRAF6 constitutively, whereas its association with IRAK-1 was seen only after hypoxia-reoxygenation. Suppression of TIFA by siRNA reduced NF-κB activation and HMGB1 upregulation and release after hypoxia-reoxygenation. Taken together, these data suggest that TIFA is involved in the regulation of cell signaling in hypoxia-reoxygenation. The increase in TIFA level appears to be a feed-forward mechanism involved in TLR4/MyD88-dependent signaling, leading to NF-κB activation and HMGB1 release.
AuthorsNing Ding, Yong Zhang, Patricia A Loughran, Qingde Wang, Allan Tsung, Timothy R Billiar
JournalFree radical biology & medicine (Free Radic Biol Med) Vol. 63 Pg. 361-7 (Oct 2013) ISSN: 1873-4596 [Electronic] United States
PMID23722163 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Adaptor Proteins, Signal Transducing
  • HMGB1 Protein
  • Interleukin-1
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • T2bp protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
Topics
  • Adaptor Proteins, Signal Transducing (genetics, metabolism)
  • Animals
  • Gene Expression Regulation
  • HMGB1 Protein (metabolism)
  • Hypoxia (metabolism, pathology)
  • Interleukin-1 (genetics, metabolism)
  • Mice
  • Myeloid Differentiation Factor 88 (metabolism)
  • Shock, Hemorrhagic (metabolism, pathology)
  • Signal Transduction (genetics)
  • Toll-Like Receptor 4 (metabolism)
  • Up-Regulation

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