title: The role of tumor necrosis factor-α and interferon-γ in regulating angiomotin-like protein 1 expression in lung microvascular endothelial cells.
abstract: BACKGROUND
  Angiogenesis in the alveolar septa is thought be a critical factor in pulmonary emphysema. Angiomotin-like protein 1 (AmotL1) is involved in angiogenesis via regulating endothelial cell function. However, the role of AmotL1 in the pathogenesis of pulmonary emphysema has not been elucidated. The objective of this study is to evaluate the expression of AmotL1 in lung tissues from a murine model with emphysema, as well as from patients with chronic obstructive pulmonary disease (COPD). Furthermore, we analyzed the regulation of AmotL1 expression by TNF-α and IFN-γ in endothelial cells in vitro.
  
  
  METHODS
  Nrf2 knockout mice were exposed to cigarette smoke (CS) for 4 weeks, and the down-regulated genes affecting vascularity in the whole lung were identified by microarray analysis. This analysis revealed that the mRNA expression of AmotL1 decreased in response to CS when compared with air exposure. To confirm the protein levels that were indicated in the microarray data, we determined the expression of AmotL1 in lung tissues obtained from patients with COPD and also determined the expression of AmotL1, NFκB and IκBα in cultured normal human lung microvascular endothelial cells (HLMVECs) that were stimulated by TNF-α and IFN-γ.
  
  
  RESULTS
  We found that the number of AmotL1-positive vessels decreased in the emphysema lungs compared with the normal and bronchial asthmatic lungs. IFN-γ pretreatment diminished the TNF-α-induced AmotL1 in the cultured HLMVECs by blocking the degradation of IκBα.
  
  
  CONCLUSIONS
  These results suggested that IFN-γ exhibits anti-angiogenesis effects by regulating the expression of TNF-α-induced AmotL1 via NFκB in emphysema lungs.
authors.affiliation: Division of Pulmonary Medicine, Allergy, and Rheumatology, Department of Internal Medicine, Iwate Medical University School of Medicine, Iwate 020-8505, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Nakajima
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Wataru
authors.initials: W
authors.lastname: Shigeeda
authors.forename: Makoto
authors.initials: M
authors.lastname: Tomoyasu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Deguchi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Tanita
authors.forename: Kohei
authors.initials: K
authors.lastname: Yamauchi
mesh_terms: D000091082:Angiomotins; D000091304:Angiopoietin-Like Protein 1; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C510063:AMOTL1 protein, human; C449807:Amotl1 protein, mouse; D000091082:Angiomotins; D000091304:Angiopoietin-Like Protein 1; C573415:IFNG protein, human; D008565:Membrane Proteins; D016328:NF-kappa B; D014028:Tobacco Smoke Pollution; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051550:I-kappa B Kinase