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* College of Biomedical Sciences, Florida Atlantic University, Boca Raton, FL 33431;
Palmeto Dr, Caswell Beach, NC 28461; and
Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27834
Over 25 years ago, it was observed that peritoneal macrophages (M
) isolated from mice given heat-killed Mycobacterium bovis bacillus Calmette-Guérin (HK-BCG) i.p. did not release PGE2. However, when peritoneal M from untreated mice are treated with HK-BCG in vitro, cyclooxygenase 2 (COX-2), a rate-limiting enzyme for PGE2 biosynthesis, is expressed and the release of PGE2 is increased. The present study of peritoneal M obtained from C57BL/6 mice and treated either in vitro or in vivo with HK-BCG was undertaken to further characterize the cellular responses that result in suppression of PGE2 release. The results indicate that M treated with HK-BCG in vivo express constitutive COX-1 and inducible COX-2 that are catalytically inactive, are localized subcellularly in the cytoplasm, and are not associated with the nuclear envelope (NE). In contrast, M treated in vitro express catalytically active COX-1 and COX-2 that are localized in the NE and diffusely in the cytoplasm. Thus, for local M activated in vivo by HK-BCG, the results indicate that COX-1 and COX-2 dissociated from the NE are catalytically inactive, which accounts for the lack of PGE2 production by local M activated in vivo with HK-BCG. Our studies further indicate that the formation of catalytically inactive COX-2 is associated with in vivo phagocytosis of HK-BCG, and is not dependent on extracellular mediators produced by in vivo HK-BCG treatment. This attenuation of PGE2 production may enhance M-mediated innate and Th1-acquired immune responses against intracellular infections which are suppressed by PGE2.
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1 This work was supported by National Institutes of Health RO1 HL71711, Department of Defense DAMD 17-03-1-0004, the Charles E. Schmidt Biomedical Foundation (to Y.S.), and Florida Atlantic University.
2 Address correspondence and reprint requests to Dr. Yoshimi Shibata, College of Biomedical Sciences, Florida Atlantic University, 777 Glades Road, P.O. Box 3091, Boca Raton, FL 33431-0991. E-mail address: yshibata{at}fau.edu
3 Abbreviations used in this paper: M, macrophage; COX, cyclooxygenase; HK, heat killed; BCG, bacillus Calmette-Guérin; NE, nuclear envelope; ER, endoplasmic reticulum; PGES, PGE synthase; cPLA2, cytosolic phospholipase A2; PI, propidium iodide; AA, arachidonic acid; TMPD, N,N,N',N'-tetramethyl-p-phenylenediamine; CFDA, carboxyfluorescein diacetate.
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  T. Shinohara, T. Pantuso, S. Shinohara, M. Kogiso, Q. N. Myrvik, R. A. Henriksen, and Y. Shibata Persistent Inactivation of Macrophage Cyclooxygenase-2 in Mycobacterial Pulmonary Inflammation Am. J. Respir. Cell Mol. Biol., August 1, 2009; 41(2): 146 - 154. [Abstract] [Full Text] [PDF]
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