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

J. Biol. Chem., Vol. 283, Issue 38, 26089-26097, September 19, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/38/26089    most recent M801902200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend 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 Takeda, Y. Articles by Kawase, I. Search for Related Content PubMed PubMed Citation Articles by Takeda, Y. Articles by Kawase, I. Social Bookmarking                      What's this?

Double Deficiency of Tetraspanins CD9 and CD81 Alters Cell Motility and Protease Production of Macrophages and Causes Chronic Obstructive Pulmonary Disease-like Phenotype in Mice^*

Yoshito Takeda¹, Ping He¹, Isao Tachibana², Bo Zhou, Kenji Miyado^¶3, Hideshi Kaneko^||, Mayumi Suzuki, Seigo Minami, Takeo Iwasaki, Sho Goya, Takashi Kijima, Toru Kumagai, Mitsuhiro Yoshida, Tadashi Osaki, Toshihisa Komori⁴, Eisuke Mekada^¶, and Ichiro Kawase

From the Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, the Department of Respiratory Medicine, the Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, 71004 China, ^¶Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan, and ^||Pharmacological and Safety Research Department, Pharmaceutical Development Research Laboratories, Teijin Pharma Limited, Tokyo 191-8512, Japan

CD9 and CD81 are closely related tetraspanins that regulate cell motility and signaling by facilitating the organization of multimolecular membrane complexes, including integrins. We show that CD9 and CD81 are down-regulated in smoking-related inflammatory response of a macrophage line, RAW264.7. When functions of CD9 and CD81 were ablated with monoclonal antibody treatment, small interfering RNA transfection, or gene knock-out, macrophages were less motile and produced larger amounts of matrix metalloproteinase (MMP)-2 and MMP-9 than control cells in vitro. In line with this, CD9/CD81 double-knock-out mice spontaneously developed pulmonary emphysema, a major pathological component of chronic obstructive pulmonary disease (COPD). The mutant lung contained an increased number of alveolar macrophages with elevated activities of MMP-2 and MMP-9 and progressively displayed enlarged airspace and disruption of elastic fibers in the alveoli. Secretory cell metaplasia, a finding similar to goblet cell metaplasia in cigarette smokers, was also observed in the epithelium of terminal bronchioles. With aging, the double-knockout mice showed extrapulmonary phenotypes, including weight loss, kyphosis, and osteopenia. These results suggest that the tetraspanins CD9 and CD81 regulate cell motility and protease production of macrophages and that their dysfunction may underlie the progression of COPD.

Received for publication, March 10, 2008 , and in revised form, July 7, 2008.

^* This work was supported by a grant from Takeda Science Foundation, Osaka, Japan (to I. T.), and a grant from "Kansai Biomedical Cluster" Project in Saito, Japan, which is promoted by the Knowledge Cluster Initiative of the Ministry of Education, Culture, Sports, Science and Technology, Japan (to I. T.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures, Figs. 1–4, Tables 1 and 2, and Video 1.

¹ Both authors contributed equally to this work.

³ Present address: Dept. of Reproductive Biology and Pathology, National Center for Child Health and Development, Tokyo 157-8535, Japan.

⁴ Present address: Division of Cell Biology, Dept. of Basic Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan.

² To whom correspondence should be addressed: Dept. of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. Tel.: 81-6-6879-3833; Fax: 81-6-6879-3839; E-mail: itachi02{at}imed3.med.osaka-u.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Suzuki, I. Tachibana, Y. Takeda, P. He, S. Minami, T. Iwasaki, H. Kida, S. Goya, T. Kijima, M. Yoshida, et al. Tetraspanin CD9 Negatively Regulates Lipopolysaccharide-Induced Macrophage Activation and Lung Inflammation J. Immunol., May 15, 2009; 182(10): 6485 - 6493. [Abstract] [Full Text] [PDF]