title: Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs.
abstract: 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.
authors.affiliation: Asthma & Allergy Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia.
authors.forename: Yuben P
authors.initials: YP
authors.lastname: Moodley
authors.forename: Neil L A
authors.initials: NL
authors.lastname: Misso
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Scaffidi
authors.forename: Mirjana
authors.initials: M
authors.lastname: Fogel-Petrovic
authors.forename: Robin J
authors.initials: RJ
authors.lastname: McAnulty
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Laurent
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thompson
authors.forename: Darryl A
authors.initials: DA
authors.lastname: Knight
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D005347:Fibroblasts / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D017370:Interleukin-11 / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000276:immunology* / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology* / Q000503:physiopathology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D017370:Interleukin-11; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D051028:bcl-2-Associated X Protein