title: Evidence for the involvement of type I interferon in pulmonary arterial hypertension.
abstract: BACKGROUND
  Evidence is increasing of a link between interferon (IFN) and pulmonary arterial hypertension (PAH). Conditions with chronically elevated endogenous IFNs such as systemic sclerosis are strongly associated with PAH. Furthermore, therapeutic use of type I IFN is associated with PAH. This was recognized at the 2013 World Symposium on Pulmonary Hypertension where the urgent need for research into this was highlighted.
  
  
  OBJECTIVE
  To explore the role of type I IFN in PAH.
  
  
  RESULTS
  Cells were cultured using standard approaches. Cytokines were measured by ELISA. Gene and protein expression were measured using reverse transcriptase polymerase chain reaction, Western blotting, and immunohistochemistry. The role of type I IFN in PAH in vivo was determined using type I IFN receptor knockout (IFNAR1(-/-)) mice. Human lung cells responded to types I and II but not III IFN correlating with relevant receptor expression. Type I, II, and III IFN levels were elevated in serum of patients with systemic sclerosis associated PAH. Serum interferon γ inducible protein 10 (IP10; CXCL10) and endothelin 1 were raised and strongly correlated together. IP10 correlated positively with pulmonary hemodynamics and serum brain natriuretic peptide and negatively with 6-minute walk test and cardiac index. Endothelial cells grown out of the blood of PAH patients were more sensitive to the effects of type I IFN than cells from healthy donors. PAH lung demonstrated increased IFNAR1 protein levels. IFNAR1(-/-) mice were protected from the effects of hypoxia on the right heart, vascular remodeling, and raised serum endothelin 1 levels.
  
  
  CONCLUSIONS
  These data indicate that type I IFN, via an action of IFNAR1, mediates PAH.
authors: From the Department of Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, United Kingdom (P.M.G., D.M.R., N.S.K., N.A.M., S.J.W., J.A.M.); Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (E.O., O.D.D., L.Z.); Service d'Anatomie Pathologique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France (P.D.); Univ. Paris-Sud, Faculté de médecine, Kremlin-Bicêtre, France (P.D., F.P., F.A., M.H.); INSERM UMR-S 999, Labex LERMIT, Hypertension Artérielle Pulmonaire: Physiopathologie et Innovation Thérapeutique, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France (P.D., F.P., F.A., E.F., M.H.); AP-HP, DHU TORINO, Centre de Référence de l'Hypertension Pulmonaire Sévère, Service de Pneumologie et Réanimation Respiratoire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France (F.P., F.A., M.H.); Pulmonary Hypertension service, Royal Free Hospital, London, United Kingdom (B.E.S., J.G.C.); Centre for Rheumatology and Connective Tissue Diseases, Department of Inflammation, University College London, Royal Free Campus, London, United Kingdom (A.M.H.); Pulmonary Vascular Diseases Unit, Papworth Hospital NHS Trust, Papworth Everard, Cambridge (M.S., G.H., N.W.M.); and National Heart & Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Centre for Respiratory Infection, Imperial College London, United Kingdom (N.B.).
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mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology; D019332:Endothelin-1 / Q000276:immunology / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D006801:Humans; D006976:Hypertension, Pulmonary / Q000276:immunology* / Q000378:metabolism; D016898:Interferon-alpha / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology
chemical_list: C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D019332:Endothelin-1; C507964:IFNAR1 protein, human; C508032:Ifnar1 protein, mouse; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta; D016899:Interferon-beta; D007371:Interferon-gamma
keywords: IFNAR1 subunit, interferon alpha-beta receptor; chemokine CXCL10; endothelin-1; inflammation; interferon type I; pulmonary arterial hypertension; scleroderma, systemic