Document Detail


The Toll-like receptor 3 L412F polymorphism and disease progression in idiopathic pulmonary fibrosis.
MedLine Citation:
PMID:  24070541     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal progressive interstitial pneumonia. The innate immune system provides a crucial function in the recognition of tissue injury and infection. Toll-like receptor 3 (TLR3) is an innate immune system receptor. We investigated the role of a functional TLR3 single-nucleotide polymorphism in IPF.
OBJECTIVES: To characterize the effects of the TLR3 Leu412Phe polymorphism in primary pulmonary fibroblasts from patients with IPF and disease progression in two independent IPF patient cohorts. To investigate the role of TLR3 in a murine model of pulmonary fibrosis.
METHODS: TLR3-mediated cytokine, type 1 IFN, and fibroproliferative responses were examined in TLR3 wild-type (Leu/Leu), heterozygote (Leu/Phe), and homozygote (Phe/Phe) primary IPF pulmonary fibroblasts by ELISA, real-time polymerase chain reaction, and proliferation assays. A murine model of bleomycin-induced pulmonary fibrosis was used in TLR3 wild-type (tlr3(+/+)) and TLR3 knockout mice (tlr3(-/-)). A genotyping approach was used to investigate the role of the TLR3 L412F polymorphism in disease progression in IPF using survival analysis and longitudinal decline in FVC.
MEASUREMENTS AND MAIN RESULTS: Activation of TLR3 in primary lung fibroblasts from TLR3 L412F-variant patients with IPF resulted in defective cytokine, type I IFN, and fibroproliferative responses. We demonstrate increased collagen and profibrotic cytokines in TLR3 knockout mice (tlr3(-/-)) compared with wild-type mice (tlr3(+/+)). TLR3 L412F was also associated with a significantly greater risk of mortality and an accelerated decline in FVC in patients with IPF.
CONCLUSIONS: This study reveals the crucial role of defective TLR3 function in promoting progressive IPF.
Authors:
David N O'Dwyer; Michelle E Armstrong; Glenda Trujillo; Gordon Cooke; Michael P Keane; Padraic G Fallon; A John Simpson; Ann B Millar; Emmet E McGrath; Moira K Whyte; Nik Hirani; Cory M Hogaboam; Seamas C Donnelly
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  188     ISSN:  1535-4970     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2013 Dec 
Date Detail:
Created Date:  2013-12-16     Completed Date:  2014-02-10     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1442-50     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Aged
Aged, 80 and over
Animals
Biological Markers / metabolism
Cohort Studies
Disease Progression*
Enzyme-Linked Immunosorbent Assay
Female
Genetic Markers
Genotype
Genotyping Techniques
Humans
Idiopathic Pulmonary Fibrosis / genetics*,  metabolism,  mortality,  pathology
Interferon Type I / metabolism
Male
Mice
Mice, Knockout
Middle Aged
Polymorphism, Single Nucleotide*
Real-Time Polymerase Chain Reaction
Survival Analysis
Toll-Like Receptor 3 / deficiency,  genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
ETM/153//Chief Scientist Office; G0901697//Medical Research Council
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Genetic Markers; 0/Interferon Type I; 0/TLR3 protein, human; 0/TLR3 protein, mouse; 0/Toll-Like Receptor 3
Comments/Corrections
Comment In:
Am J Respir Crit Care Med. 2013 Dec 15;188(12):1392-4   [PMID:  24328772 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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