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Published ahead of print on April 24, 2003, doi:10.1165/rcmb.2002-0262OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 4, October 2003, 490-498

A more recent version of this article appeared on October 1, 2003
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Submitted on November 22, 2002
Revised on April 23, 2003

INVERSE EFFECTS OF IL-6 ON APOPTOSIS OF FIBROBLASTS FROM PULMONARY FIBROSIS AND NORMAL LUNGS

Yuben P Moodley1, Neil L Misso1, Amelia K Scaffidi1, Mirjana Fogel-Petrovic1, Robin J McAnulty2, Geoffrey J Laurent2, Philip J Thompson1, and Darryl A Knight1*

1 Asthma & Allergy Research Institute, Nedlands, Western Australia, Australia; Medicine, University of Western Australia, Nedlands, Western Australia, Australia, 2 Center for Cardiopulmonary Biochemistry and Respiratory Medicine, Royal Free and University College Medical School, University College London, London, United Kingdom

* To whom correspondence should be addressed. 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. Since 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 3 patients with IPF (IPF-Fb) and 3 subjects without lung disease (normal-Fb). IPF-Fb were resistant to Fas induced apoptosis compared with normal-Fb (p < 0.01). Using Ribonuclease 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 ERK had no effect in normal-Fb but reversed the anti-apoptotic 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 pro-fibrotic effect of IL-6 in IPF.




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