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 Google Scholar Google Scholar Articles by Hartl, D. Articles by Elias, J. A. Search for Related Content PubMed PubMed Citation Articles by Hartl, D. Articles by Elias, J. A.

Acidic Mammalian Chitinase Regulates Epithelial Cell Apoptosis via a Chitinolytic-Independent Mechanism

Dominik Hartl^*, Chuan Hua He^*, Babara Koller^*, Carla A. Da Silva^*, Yasushi Kobayashi, Chun Geun Lee^*, Richard A. Flavell and Jack A. Elias^1,*

^* Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, Department of Internal Medicine, New Haven, CT 06520; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and Howard Hughes Medical Institute, Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520

Acidic mammalian chitinase (AMCase) is produced during and plays an important role in the pathogenesis of Th2-mediated diseases and antiparasite responses. However, the effector responses of AMCase in these settings have not been adequately defined and the relationship(s) between its chitinolytic and other biologic properties have not been investigated. In these studies, we demonstrate that AMCase protects airway epithelial cells from Fas ligand- and growth factor withdrawal-induced apoptosis. This cytoprotection was associated with Akt phosphorylation and abrogated when the PI3K/Akt pathway was inhibited. Comparable cytoprotection was also seen in experiments comparing wild-type AMCase and mutant AMCase that lacked chitinolytic activity. Importantly, the apoptosis-inhibiting effect of enzymatically active and inactive AMCase was abrogated by treatment with allosamidin. These studies demonstrate that secreted AMCase feeds back in an autocrine and/or paracrine manner to protect pulmonary epithelial cells from growth factor withdrawal- and Fas ligand-induced apoptosis. They also demonstrate that the cytoprotection is mediated via a PI3K/Akt-dependent and allosamidin-sensitive pathway that is independent of the chitinolytic activity of this chitinase.

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 Address correspondence and reprint requests to: Prof. Jack A. Elias, Yale University School of Medicine, Section of Pulmonary and Critical Care Medicine, 333 Cedar Street (1072 LMP), New Haven, CT 06520-8056. E-mail address: jack.elias{at}yale.edu

² Abbreviations used in this paper: AMCase, acidic mammalian chitinase; WT, wild type; FasL, Fas ligand; w/v, weight to volume ratio; MFI, mean fluorescence intensity; PI, propidium iodide; BRP-39, breast regression protein –39.