title: Tumor necrosis factor superfamily 14 (LIGHT) controls thymic stromal lymphopoietin to drive pulmonary fibrosis.
abstract: BACKGROUND
  Pulmonary fibrosis is characterized by excessive accumulation of collagen and α-smooth muscle actin in the lung. The key molecules that promote these phenotypes are of clinical interest.
  
  
  OBJECTIVE
  Thymic stromal lymphopoietin (TSLP) has been found at high levels in patients with asthma and idiopathic pulmonary fibrosis, and TSLP has been proposed as a primary driver of lung fibrotic disease. We asked whether tumor necrosis factor superfamily protein 14 (TNFSF14) (aka LIGHT) controls TSLP production to initiate fibrosis.
  
  
  METHODS
  Expression of TSLP and initiation of pulmonary fibrosis induced by bleomycin were assessed in mice deficient in LIGHT. The ability of recombinant LIGHT, given intratracheally to naive mice, to promote TSLP and fibrosis was also determined.
  
  
  RESULTS
  Genetic deletion of LIGHT abolished lung TSLP expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and α-smooth muscle actin. Furthermore, recombinant LIGHT administered in vivo induced lung expression of TSLP in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a TSLP-dependent manner. Blockade of LIGHT binding to either of its receptors, herpes virus entry mediator and lymphotoxin beta receptor, inhibited clinical symptoms of pulmonary fibrosis, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of TSLP. Moreover, LIGHT induced TSLP directly in human bronchial epithelial cells and synergized with IL-13 and TGF-β in vivo to promote TSLP in the lungs and drive fibrosis.
  
  
  CONCLUSIONS
  These results show that LIGHT is a profibrogenic cytokine that may be a key driver of TSLP production during the initiation and development of lung fibrotic disease.
authors: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, Calif.
authors: Rana
authors: R
authors: Herro
authors: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, Calif.
authors: Ricardo
authors: R
authors: Da Silva Antunes
authors: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, Calif.
authors: Amelia Roman
authors: AR
authors: Aguilera
authors: Department of Immunology, Yamaguchi University School of Medicine, Yamaguchi, Japan.
authors: Koji
authors: K
authors: Tamada
authors: Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, La Jolla, Calif. Electronic address: mick@lji.org.
authors: Michael
authors: M
authors: Croft
mesh_terms: D000199:Actins / Q000235:genetics / Q000276:immunology; D000818:Animals; D001761:Bleomycin; D002460:Cell Line; D003094:Collagen / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D006564:Herpesviridae / Q000276:immunology; D006801:Humans; D008168:Lung / Q000276:immunology* / Q000473:pathology; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D011991:Receptors, Virus / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000235:genetics / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000199:Actins; D016207:Cytokines; D053259:Lymphotoxin beta Receptor; D011991:Receptors, Virus; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; C544013:alpha-smooth muscle actin, mouse; D001761:Bleomycin; D003094:Collagen; D000094632:Thymic Stromal Lymphopoietin
keywords: HVEM; IPF; LIGHT; Pulmonary fibrosis; TNFSF14; TSLP; asthma; bronchial epithelial cell