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J. Biol. Chem., Vol. 280, Issue 50, 41137-41145, December 16, 2005

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Catalase Plays a Critical Role in the CSF-independent Survival of Human Macrophages via Regulation of the Expression of BCL-2 Family^*

Iwao Komuro, Tomoyoshi Yasuda¶, Aikichi Iwamoto, and Kiyoko S. Akagawa1

From the Departments of Immunology and ^¶Parasitology, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo 162-8640 and Division of Infectious Diseases, the Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Shiroganedai 4-6-1, Minato-ku, Tokyo 108-8639, Japan

M-colony-stimulating factor (M-CSF)-induced monocyte-derived macrophages (M-M) required continuous presence of M-CSF for their survival, and depletion of M-CSF from the culture induced apoptosis, whereas human alveolar macrophages (A-M) and granulocyte-macrophage (GM)-CSF-induced monocyte-derived macrophages (GM-M) survived even in the absence of CSF. The expression of BCL-2 was higher in M-M, and M-CSF withdrawal down-regulated the expression. The expression of BCL-X_L was higher in A-M and GM-M, and the expression was CSF-independent. The expression of MCL-1 and BAX were not different between M-M and GM-M and were CSF-independent. Down-regulation of the expression of BCL-2 and BCL-X_L by RNA interference showed the important role of BCL-2 and BCL-X_L in the survival of M-M and GM-M, respectively. Human erythrocyte catalase (HEC) and conditioned medium obtained from GM-M or A-M cultured in the absence of GM-CSF prevented the M-M from apoptosis and restored the expression of BCL-2. The activity of the conditioned medium was abrogated by pretreatment with anti-HEC antibody. Anti-HEC antibody also induced the apoptosis of M-M cultured in the presence of M-CSF and GM-M and A-M cultured in the presence or absence of GM-CSF and down-regulated the expression of BCL-2 and BCL-X_L in these Ms. GM-M and A-M, but not M-M, can produce both extracellular catalase and cell-associated catalase in a CSF-independent manner. Intracellular glutathione levels were kept equivalent in these Ms, both in the presence or absence of CSF. These results indicate a critical role of extracellular catalase in the survival of human macrophages via regulation of the expression of BCL-2 family genes.

Received for publication, September 7, 2005 , and in revised form, September 19, 2005.

^* This study was supported in part by grants for Research on Health Sciences Focusing on Drug Innovation from the Japan Health Sciences Foundation and the Ministry of Health, Labor, and Welfare of Japan. 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 To whom correspondence should be addressed. Tel.: 81-3-5285-1111; Fax: 81-3-5285-1150; E-mail: akagawak{at}nih.go.jp.

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