Inverse effects of interleukin-6 on apoptosis of fibroblasts from pulmonary fibrosis and normal lungs.
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.
Moodley
Yuben P
YP
Asthma & Allergy Research Institute, Sir Charles Gairdner Hospital, Nedlands, Western Australia.
Misso
Neil L A
NL
Scaffidi
Amelia K
AK
Fogel-Petrovic
Mirjana
M
McAnulty
Robin J
RJ
Laurent
Geoffrey J
GJ
Thompson
Philip J
PJ
Knight
Darryl A
DA
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
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