Journal Article


Seamas C Donnelly
Cory M Hogaboam
Nik Hirani
Moira K Whyte
Emmet E McGrath
Ann B Millar
A John Simpson
Padraic G Fallon
Michael P Keane
Gordon Cooke
and 3 others



toll like receptor 3 toll like receptor pulmonary disease immune system idiopathic pulmonary fibrosis mice knockout disease progression real time polymerase chain reaction

The Toll-like Receptor 3 L412F Polymorphism and Disease Progression in Idiopathic Pulmonary Fibrosis. (2013)

Abstract 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.
Collections Ireland -> University College Dublin -> PubMed

Full list of authors on original publication

Seamas C Donnelly, Cory M Hogaboam, Nik Hirani, Moira K Whyte, Emmet E McGrath, Ann B Millar, A John Simpson, Padraic G Fallon, Michael P Keane, Gordon Cooke and 3 others

Experts in our system

Seamas C Donnelly
TU Dublin (Tallaght Campus)
Total Publications: 35
Padraic Fallon
Trinity College Dublin
Total Publications: 154
Michael P Keane
University College Dublin
Total Publications: 23
Gordon Cooke
TU Dublin (Tallaght Campus)
Total Publications: 20