Tumor necrosis factor superfamily 14 (LIGHT) controls thymic stromal lymphopoietin to drive pulmonary fibrosis - 04/09/15
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.
Objectives |
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.
Le texte complet de cet article est disponible en PDF.Key words : Pulmonary fibrosis, asthma, IPF, bronchial epithelial cell, TNFSF14, LIGHT, TSLP, HVEM
Abbreviations used : AOI, aSMA, ECM, IPF, LIGHT, TNFSF, TSLP, WT
Plan
This work was supported by the National Institutes of Health (grant nos. AI070535 and AI100905 to M.C.). |
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Disclosure of potential conflict of interest: K. Tamada has received research support from the Japanese government, has received payment for lectures from the Japanese Cancer Association, and has received payment for reviewing manuscripts from Japanese: Gann to Kagaku Ryoho, Rinsho Ketsueki. M. Croft has received research support from the National Institutes of Health and Janssen Research & Development, LLC and has consultant arrangements with Tanabe Research Labs and Debiopharm Intl SA. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 136 - N° 3
P. 757-768 - septembre 2015 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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