Role of HIF-1 in the regulation of inflammatory responses through sensing alterations in microenvironments of immune cells

• Project/Area Number: 17570119
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Keio University
• Principal Investigator: GODA Nobuhito Keio University, Department of Medicine, Associate Professor, 医学部, 講師 (00245549)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: cytokines / inflammation / T lymphocytes / acetaminophen / hypoxic stress / HIF-1 / colitis / 遺伝子改変 / 粘膜免疫 / リンパ球分化・発達 / 転写発現制御

Research Abstract

When an inflammation occurs, immune cells migrate from well-oxygenated blood vessels to hypoxic inflamed sites, where they regulate inflammatory responses despite limited oxygen available for the cells to exert their diverse functions. As hypoxia itself is not optimal for immune cells to function, the cells sense and adapt to the alteration of oxygen concentrations in their environments. The adaptive responses to hypoxia are largely achieved by an activation of a well-conserved nuclear transcription factor, hypoxia inducible factor-1 (HIF-1). In this study, we provide direct evidence for role of HIF-1 as a negative regulator in the control of inflammatory responses. Transfer of HIF-1α-deficient naive T cells (CD4^+CD45Rb^<high>) into immunodeficient Rag2 KO mice evoked severer colitis with higher accumulation of inflammatory cells in lamina propria than that of wild type T cells. Accumulated HIF-1a-deficient T cells in the inflamed tissues produced inflammatory cytokines comparable to wild type T cells, suggesting an involvement of unraveled HIF-1-mediated but cytokine-independent mechanisms in the progression of APAP-hepatitis. On the other hand, exposure of mice lacking HIF-1 α gene in T cells to acetaminophen (APAP), which is known to cause T cell-mediated hepatitis, resulted in higher lethality compared to that of wild type mice. Deletion of T cells with anti-CD4 neutralizing antibody completely abolished the APAP-induced mortality in the mutant mice, confirming an involvement of T cells in APAP-induced hepatitis. Collectively, these results suggest that HIF-1 suppresses excessive inflammatory responses and thus serves as a negative regulator for T cell-mediated immune systems. Further investigation is needed to elucidate precious molecular mechanisms for roles of HIF-1 in the regulation of T cell functions, and will shed light on the development of a new therapeutic strategy for inflammation by targeting the oxygen sensing and adaptive systems.

Research Products

• [Journal Article] Erythrocytes with T-state-stabilized hemoglobin as a therapeutic tool for postischemic liver dysfunction. (2006)
  • Author(s): Suganuma, K., et al.
  • Journal Title: Antioxid Redox Signal. 8 Pages: 1847-1855
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Erythrocytes with T-state-stabilized hemoglobin as a therapeutic tool for postischemic liver dysfunction (2006)
  • Author(s): Suganuma, K., Tsukada, K., Kashiba, M., Tsuneshige, A., Furukawa, T., Kubota, T., Goda, N., Kitajima, M., Yonetani, T., Suematsu, M.
  • Journal Title: Antioxid. Redox Signal. 8 Pages: 18741-1855
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hydrogen sulfide as an endogenous modulator of biliary bicarbonate excretion in the rat liver. (2005)
  • Author(s): Fujii, K., et al.
  • Journal Title: Antioxid Redox Signal. 7 Pages: 788-794
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cadmium exposure alters metabolomics of sulfur-containing amino acids in rat testes. (2005)
  • Author(s): Sugiura, Y., et al.
  • Journal Title: Antioxid Redox Signal. 7 Pages: 781-787
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Carbon monoxide as a guardian against hepatobiliary dysfunction. (2005)
  • Author(s): Suematsu, M., et al.
  • Journal Title: Alcohol Clin. Exp. Res. 29
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Carbon monoxide from heme oxygenase-2 is a tonic regulator against NO-dependent vasodilatation in the adult rat cerebral microcirculation. (2005)
  • Author(s): Ishikawa, M., et al.
  • Journal Title: Circ. Res. 97
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Carbon monoxide from heme oxygenase-2 is a tonic regulator against NO-dependent vasodilatation in the adult rat cerebral microcirculation (2005)
  • Author(s): Ishikawa, M., Kajimura, M., Adachi, T., Maruyama, K., Makino, N., Goda, N., Yamaguchi, T., Sekizuka, E., Suematsu, M.
  • Journal Title: Circ.Res. 97
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Carbon monoxide as a guardian against hepatobiliary dysfunction (2005)
  • Author(s): Suematsu, M., Tsukada, K., Tajima, T., Yamamoto, T., Ochiai, D., Watanabe, H., Yoshimura, Y., Goda.N.
  • Journal Title: Alcohol Clin. Exp. Res. 29
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cadmium exposure alters metabolomics of sulfur-containing amino acids in rat testes (2005)
  • Author(s): Sugiura, Y., Kashiba, M., Maruyama, K., Hoshikawa, K., Sasaki, R., Saito, K., Kimura, H., Goda, N., Suematsu, M.
  • Journal Title: Antioxid. Redox Signal. 7 Pages: 781-787
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hydrogen sulfide as an endogenous modulator of biliary bicarbonate excretion in the rat liver (2005)
  • Author(s): Fujii, K., Sakuragawa, T., Kashiba, M., Sugiura, Y., Kondo, M., Maruyama, K., Goda, N., Nimura, Y., Suematsu, M.
  • Journal Title: Antioxid Redox Signal. 7 Pages: 788-794
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Carbon monoxide as a guardian against hepatobiliary dysfunction. (2005)
  • Author(s): Suematsu, M., et al.
  • Journal Title: Alcohol Clin.Exp.Res. 29
• [Journal Article] Carbon monoxide from heme oxygenase-2 is a tonic regulator against NO-dependent vasodilatation in the adult rat cerebral microcirculation. (2005)
  • Author(s): Ishikawa, M., et al.
  • Journal Title: Circ.Res. 97
• [Book] 炎症と免疫 (2005)
  • Author(s): 合田亘人, 槌谷夏子, 山本雄大
  • Total Pages: 140
  • Publisher: 先端医学社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 肝・消化管と低酸素 (2005)
  • Author(s): 合田亘人, 槌谷夏子, 山本雄大
  • Total Pages: 7
  • Publisher: 先端医学社