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Inverse Effects of Interleukin-6 on Apoptosis of Fibroblasts from Pulmonary Fibrosis and Normal Lungs

Asthma and Allergy Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia; School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia; and Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, Royal Free and University College Medical School, University College London, London, United Kingdom

Address correspondence to: Dr. Darryl Knight, Asthma & Allergy Research Institute, Ground Floor, "E" Block, Sir Charles Gairdner Hospital, Verdun Street, Nedlands, Western Australia, 6009. E-mail: dknight{at}cyllene.uwa.edu.au

Fibroblast apoptosis is crucial to the resolution of fibrosis. However, the mechanisms by which these cells undergo apoptosis are not well known. Because interleukin (IL)-6 and IL-11 may alter repair and remodeling processes, we hypothesized that they may play a role in idiopathic pulmonary fibrosis (IPF). We investigated the effects of these cytokines on Fas-induced apoptosis using primary lung fibroblasts from three patients with IPF (IPF-Fb) and three subjects without lung disease (normal-Fb). IPF-Fb were resistant to Fas-induced apoptosis compared with normal-Fb (P < 0.01). Using RNase protection assays, we showed that IL-6 enhanced Fas-induced apoptosis and expression of Bax in normal-Fb, but inhibited apoptosis and induced expression of Bcl-2 in IPF-Fb. Densitometry of Western blots revealed a Bcl-2/Bax ratio 0.15 ± 0.01 in normal-Fb compared with 12.05 ± 1.0 in IPF-Fb. Upregulation of Bcl-2 in normal-Fb and Bax in IPF-Fb were both STAT-3–dependent. Inhibition of extracellular signal–regulated kinase had no effect in normal-Fb, but reversed the antiapoptotic effect of IL-6 in IPF-Fb. IL-11 inhibited Fas-induced apoptosis and increased Bcl-2 expression in both normal-Fb and IPF-Fb. These results suggest that altered IL-6 signaling in IPF-Fb may enhance the resistance of these cells to apoptosis and contribute to a profibrotic effect of IL-6 in IPF.

Abbreviations: -smooth muscle actin, -SMA • antisense oligonucleotides, ASON • Dulbecco's modified Eagle's medium, DMEM • extracellular matrix, ECM • extracellular regulated kinase, ERK • fibroblasts derived from the lungs of patients with IPF, IPF-Fb • glycoprotein 130, gp130 • idiopathic pulmonary fibrosis, IPF • interleukin, IL • janus kinases, JAK • matrix metalloproteinase, MMP • fibroblasts derived from the lungs of patients without IPF, normal-Fb • phosphate-buffered saline, PBS • propidium iodide, PI • ribonuclease protection assay, RPA • signal transducer and activator of transcription, STAT • tissue inhibitor of metalloproteinase, TIMP • usual interstitial pneumonia, UIP

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