HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stout, B. A. Articles by Tesfaigzi, Y. Search for Related Content PubMed PubMed Citation Articles by Stout, B. A. Articles by Tesfaigzi, Y.

STAT1 Activation Causes Translocation of Bax to the Endoplasmic Reticulum during the Resolution of Airway Mucous Cell Hyperplasia by IFN-¹

Barbara A. Stout^*, Karla Melendez^*, JeanClare Seagrave^*, Michael J. Holtzman, Bridget Wilson, Jialing Xiang and Yohannes Tesfaigzi^2,*

^* Lovelace Respiratory Research Institute, Albuquerque, NM 87185; Pulmonary and Critical Care Divisions, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131; and Department of Biological, Chemical, and Physical Science, Illinois Institute of Technology, Chicago, IL 60616

Disruption of the normal resolution process of inflammation-induced mucous cell hyperplasia may lead to sustained mucous hypersecretion in chronic diseases. During prolonged exposure of mice to allergen, IFN- reduces mucous cell hyperplasia, but the signaling responsible for the cell death is largely unknown. A brief phosphorylation of STAT1 by IFN- was required for cell death in airway epithelial cells (AEC), and during prolonged exposure to allergen, mucous cell hyperplasia remained elevated in STAT1^–/– but was resolved in STAT1^+/+ mice. Although IFN- treatment of primary human AECs and other airway cell lines left Bax protein levels unchanged, it caused translocation of Bax from the cytosol to the endoplasmic reticulum (ER) but not to the mitochondria. Localization of Bax to the ER was observed in IFN--treated primary AECs isolated from STAT1^+/+ mice but not in cells from STAT1^–/– mice. In addition, ER Bax was detected in mucous cells of STAT1^+/+ but not STAT1^–/– airways of mice exposed to allergen for prolonged periods. IFN- did not release cytochrome c from mitochondria but reduced ER calcium stores and dilated the ER, confirming that the IFN--induced cell death is mediated through changes localized in the ER. Collectively, these observations suggest that STAT1-dependent translocation of Bax to the ER is crucial for IFN--induced cell death of AECs and the resolution of allergen-induced mucous cell hyperplasia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants HL68111 and ES09237 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Yohannes Tesfaigzi, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108. E-mail address: ytesfaig{at}lrri.org

³ Abbreviations used in this paper: MCH, mucous cell hyperplasia; ER, endoplasmic reticulum; NHBEC, normal human bronchial epithelial cell; ARC, airway epithelial cell.

This article has been cited by other articles:

				Y. A. Mebratu, B. F. Dickey, C. Evans, and Y. Tesfaigzi The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFN{gamma}-induced cell death J. Cell Biol., November 3, 2008; 183(3): 429 - 439. [Abstract] [Full Text] [PDF]

				K. Schwalm, J. F. Stevens, Z. Jiang, M. R. Schuyler, R. Schrader, S. H. Randell, F. H. Y. Green, and Y. Tesfaigzi Expression of the proapoptotic protein Bax is reduced in bronchial mucous cells of asthmatic subjects Am J Physiol Lung Cell Mol Physiol, June 1, 2008; 294(6): L1102 - L1109. [Abstract] [Full Text] [PDF]