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(Chest. 2003;123:372S-373S.)
© 2003 American College of Chest Physicians

Interferon-{gamma} Reduces Interleukin-4– and Interleukin-13–Augmented Transforming Growth Factor-ß2 Production in Human Bronchial Epithelial Cells by Targeting Smads*

Fu-Qiang Wen, MD, PhD; Xiangde D. Liu, MD; Yusuke Terasaki; Qiuhong H. Fang, MD, PhD; Tetsu Kobayashi, MD, PhD; Shinji Abe, MD, PhD and Stephen I. Rennard, MD, FCCP

* From the Pulmonary and Critical Care Medicine Section, University of Nebraska Medical Center, Omaha, NE.

Correspondence to: Stephen I. Rennard, MD, FCCP, Pulmonary and Critical Care Medicine Section, University of Nebraska Medical Center, 985125 Nebraska Medical Center, Omaha, NE 68198-5125; e-mail: srennard{at}unmc.edu

The T-helper type 2 (Th2) cytokines, interleukin (IL)-4 and IL-13, and the T-helper type 1 cytokine interferon (IFN)-{gamma} act differently in regulating airway inflammation and subepithelial fibrosis. The production of transforming growth factor (TGF)-ß by airway epithelium and lung mesenchymal cells may be an important event in airway inflammation and remodeling. We hypothesized, therefore, that Th2 and T-helper type 1 cytokines may differentially regulate TGF-ß production and may target TGF-ß signaling.

Human bronchial epithelial cells (HBECs) and human fetal lung (HFL)-1 fibroblasts were incubated for 6 to 48 h with varying concentrations of IL-4 or IL-13 in the absence or presence of IFN-{gamma}. Postculture media were assayed for TGF-ßs. TGF-ß messenger RNA was evaluated by quantitative real-time polymerase chain reaction. Cellular localization of Smads 2, 3, 4, 7, Stat1{alpha} p91 and Stat1 p84/p91, and Stat6 were evaluated by immuno-staining.

In HBECs, IL-4 and IL-13 alone significantly enhanced the production of both active and latent forms of TGF-ß2 as detected by enzyme-linked immunosorbent assay in a time- and dose-dependent manner (p < 0.01) and augmented messenger RNA expression of TGF-ß2: 970 ± 20 x 105 vs 4,700 ± 500 x 105 glyceraldehyde-3-phosphate dehydrogenase (GAPDH) units for IL-4; 970 ± 20 x 105 vs 3,900 ± 230 x 105 GAPDH units for IL-13 (p < 0.01). In contrast, release of TGF-ßs by HFL-1 fibroblasts was not affected. IFN-{gamma} dose-dependently inhibited spontaneous TGF-ß2 release as well as IL-4– or IL-13–augmented production of TGF-ß2 in HBECs (p < 0.01). Correspondingly, IFN-{gamma} significantly reduced both basal (970 ± 20 x 105 vs 360 ± 30 x 105 GAPDH units) and IL-4– or IL-13–augmented messenger RNA expression of TGF-ß2 (4,700 ± 500 x 105 vs 570 ± 20 x 105 GAPDH units for IL-4; 3,900 ± 230 x 105 vs 560 ± 20 x 105 GAPDH units for IL-13) in HBECs (p < 0.01), but had little effect on TGF-ß messenger RNA expression in HFL-1 fibroblasts. A clear translocation of Stat1 and Stat6 from cytoplasma into the nucleus were observed in both HBECs and HFL-1 fibroblasts treated with IFN-{gamma} or IL-4 and IL-13, respectively. However, only in HBECs did IFN-{gamma} induce a clear paranuclear immunfluorescence for Smad 7. This was associated with significantly reduced nuclear localization of Smad 2, 3, and 4, all of which were induced by IL-4 and IL-13. In contrast, IFN-{gamma} had little effect on nuclear localization of Stat6.

IFN-{gamma} may attenuate IL-4– and IL-13–enhanced TGF-ß2 production in bronchial epithelial cells by targeting Smads signaling. Moreover, by inducing production of the inhibitory Smad, Smad 7, IFN-{gamma} may interfere with TGF-ß signaling. The inhibitory effect of IFN-{gamma} on TGF-ß2 production by HBECs stimulated by Th2 cytokines may play an important role in modulating airway repair.


   Footnotes
 
Abbreviations: HBEC = human bronchial epithelial cell; HFL = human fetal lung; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; IFN = interferon; IL = interleukin; TGF = transforming growth factor; Th2 = T-helper type 2





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