The Journal of Immunology, Vol 150, Issue 11 5080-5085, Copyright © 1993 by American Association of Immunologists

ARTICLES

Nitric oxide-mediated apoptosis in murine peritoneal macrophages

JE Albina, S Cui, RB Mateo and JS Reichner
Department of Surgery, Rhode Island Hospital, Providence 02903.

Nitric oxide (NO) synthase, the enzyme responsible for the generation of the cytotoxic compound NO from L-arginine, is induced in macrophages during activation. Previous work demonstrated that the cytotoxicity of NO extends to the macrophages that produce it, because the activity of NO synthase in these cells correlates inversely with their life span in culture. Data presented here demonstrate that the NO-dependent death of murine peritoneal macrophages activated in vitro with IFN-gamma and LPS is mediated through apoptosis. Evidence in this direction was provided by microscopic examination of the cells, which revealed the presence of nuclear and cytoplasmic alterations characteristic of apoptosis, and by the specific pattern of internucleosomal DNA fragmentation detected by electrophoresis. That these alterations resulted from the production of NO was confirmed by the preventive effects of cell activation in L- arginine-restricted medium or in medium containing an inhibitor of NO synthase, NG-monomethy L-arginine, and more directly by the induction of apoptosis by exposure of the cells to authentic NO gas. Additional results demonstrated that glucose starvation, the inhibition of the tricarboxylic acid cycle with fluorocitrate or of glycolysis with iodoacetate, but not the suppression of the electron transport chain with potassium cyanide, also induced macrophage apoptosis. The potential role of metabolic inhibition as a mechanism for NO-mediated apoptosis, as well as the relationship of these findings with events occurring in wounds and other sites of macrophage infiltration are discussed.

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				M.-L. Peyot, A.-P. Gadeau, F. Dandre, I. Belloc, F. Dupuch, and C. Desgranges Extracellular Adenosine Induces Apoptosis of Human Arterial Smooth Muscle Cells via A2b-Purinoceptor Circ. Res., January 7, 2000; 86(1): 76 - 85. [Abstract] [Full Text] [PDF]

				I. Angulo, F. G. de las Heras, J. F. Garcia-Bustos, D. Gargallo, M. A. Munoz-Fernandez, and M. Fresno Nitric oxide-producing CD11b+Ly-6G(Gr-1)+CD31(ER-MP12)+ cells in the spleen of cyclophosphamide-treated mice: implications for T-cell responses in immunosuppressed mice Blood, January 1, 2000; 95(1): 212 - 220. [Abstract] [Full Text] [PDF]

				M. A. Arstall, D. B. Sawyer, R. Fukazawa, and R. A. Kelly Cytokine-Mediated Apoptosis in Cardiac Myocytes : The Role of Inducible Nitric Oxide Synthase Induction and Peroxynitrite Generation Circ. Res., October 29, 1999; 85(9): 829 - 840. [Abstract] [Full Text] [PDF]

				K. Nomura, H. Imai, T. Koumura, M. Arai, and Y. Nakagawa Mitochondrial Phospholipid Hydroperoxide Glutathione Peroxidase Suppresses Apoptosis Mediated by a Mitochondrial Death Pathway J. Biol. Chem., October 8, 1999; 274(41): 29294 - 29302. [Abstract] [Full Text] [PDF]

				A. von Knethen, D. Callsen, and B. Brune Superoxide Attenuates Macrophage Apoptosis by NF-{kappa}B and AP-1 Activation That Promotes Cyclooxygenase-2 Expression J. Immunol., September 1, 1999; 163(5): 2858 - 2866. [Abstract] [Full Text] [PDF]

				D. J. Pinsky, W. Aji, M. Szabolcs, E. S. Athan, Y. Liu, Y. M. Yang, R. P. Kline, K. E. Olson, and P. J. Cannon Nitric oxide triggers programmed cell death (apoptosis) of adult rat ventricular myocytes in culture Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H1189 - H1199. [Abstract] [Full Text] [PDF]

				G. A. Martins, L. Q. Vieira, F. Q. Cunha, and J. S. Silva Gamma Interferon Modulates CD95 (Fas) and CD95 Ligand (Fas-L) Expression and Nitric Oxide-Induced Apoptosis during the Acute Phase of Trypanosoma cruzi Infection: a Possible Role in Immune Response Control Infect. Immun., August 1, 1999; 67(8): 3864 - 3871. [Abstract] [Full Text] [PDF]

				R. K. Srivastava, S. J. Sollott, L. Khan, R. Hansford, E. G. Lakatta, and D. L. Longo Bcl-2 and Bcl-XL Block Thapsigargin-Induced Nitric Oxide Generation, c-Jun NH2-Terminal Kinase Activity, and Apoptosis Mol. Cell. Biol., August 1, 1999; 19(8): 5659 - 5674. [Abstract] [Full Text] [PDF]

				S. Glockzin, A. von Knethen, M. Scheffner, and B. Brune Activation of the Cell Death Program by Nitric Oxide Involves Inhibition of the Proteasome J. Biol. Chem., July 9, 1999; 274(28): 19581 - 19586. [Abstract] [Full Text] [PDF]

				S. Nabeshima, M. Nomoto, G. Matsuzaki, K. Kishihara, H. Taniguchi, S.-i. Yoshida, and K. Nomoto T-Cell Hyporesponsiveness Induced by Activated Macrophages through Nitric Oxide Production in Mice Infected with Mycobacterium tuberculosis Infect. Immun., July 1, 1999; 67(7): 3221 - 3226. [Abstract] [Full Text] [PDF]

				A. Orlofsky, R. D. Somogyi, L. M. Weiss, and M. B. Prystowsky The Murine Antiapoptotic Protein A1 Is Induced in Inflammatory Macrophages and Constitutively Expressed in Neutrophils J. Immunol., July 1, 1999; 163(1): 412 - 419. [Abstract] [Full Text] [PDF]

				K. Wright, G. Kolios, J. Westwick, and S. G. Ward Cytokine-induced Apoptosis in Epithelial HT-29 Cells Is Independent of Nitric Oxide Formation. EVIDENCE FOR AN INTERLEUKIN-13-DRIVEN PHOSPHATIDYLINOSITOL 3-KINASE-DEPENDENT SURVIVAL MECHANISM J. Biol. Chem., June 11, 1999; 274(24): 17193 - 17201. [Abstract] [Full Text] [PDF]

				A. Hirano, Z. Yang, Y. Katayama, J. Korte-Sarfaty, and T. C. Wong Human CD46 Enhances Nitric Oxide Production in Mouse Macrophages in Response to Measles Virus Infection in the Presence of Gamma Interferon: Dependence on the CD46 Cytoplasmic Domains J. Virol., June 1, 1999; 73(6): 4776 - 4785. [Abstract] [Full Text]

				Y. Takeda, M. Tashima, A. Takahashi, T. Uchiyama, and T. Okazaki Ceramide Generation in Nitric Oxide-induced Apoptosis. ACTIVATION OF MAGNESIUM-DEPENDENT NEUTRAL SPHINGOMYELINASE VIA CASPASE-3 J. Biol. Chem., April 9, 1999; 274(15): 10654 - 10660. [Abstract] [Full Text] [PDF]

				C.-D. Jun, C.-D. Oh, H.-J. Kwak, H.-O. Pae, J.-C. Yoo, B.-M. Choi, J.-S. Chun, R.-K. Park, and H.-T. Chung Overexpression of Protein Kinase C Isoforms Protects RAW 264.7 Macrophages from Nitric Oxide-Induced Apoptosis: Involvement of c-Jun N-Terminal Kinase/Stress-Activated Protein Kinase, p38 Kinase, and CPP-32 Protease Pathways J. Immunol., March 15, 1999; 162(6): 3395 - 3401. [Abstract] [Full Text] [PDF]

				L. Rossig, B. Fichtlscherer, K. Breitschopf, J. Haendeler, A. M. Zeiher, A. Mulsch, and S. Dimmeler Nitric Oxide Inhibits Caspase-3 by S-Nitrosation in Vivo J. Biol. Chem., March 12, 1999; 274(11): 6823 - 6826. [Abstract] [Full Text] [PDF]

				A. Huwiler, J. Pfeilschifter, and H. van den Bosch Nitric Oxide Donors Induce Stress Signaling via Ceramide Formation in Rat Renal Mesangial Cells J. Biol. Chem., March 12, 1999; 274(11): 7190 - 7195. [Abstract] [Full Text] [PDF]

				B.-Y. Wang, H.-K. V. Ho, P. S. Lin, S. P. Schwarzacher, M. J. Pollman, G. H. Gibbons, P. S. Tsao, and J. P. Cooke Regression of Atherosclerosis : Role of Nitric Oxide and Apoptosis Circulation, March 9, 1999; 99(9): 1236 - 1241. [Abstract] [Full Text] [PDF]

				Z. Mallat, C. Heymes, J. Ohan, E. Faggin, G. Leseche, and A. Tedgui Expression of Interleukin-10 in Advanced Human Atherosclerotic Plaques : Relation to Inducible Nitric Oxide Synthase Expression and Cell Death Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 611 - 616. [Abstract] [Full Text] [PDF]

				J. M. Bosmans, C. J. Vrints, M. M. Kockx, H. Bult, K. M. C. Cromheeke, and A. G. Herman Continuous Perivascular L-Arginine Delivery Increases Total Vessel Area and Reduces Neointimal Thickening After Experimental Balloon Dilatation Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 767 - 776. [Abstract] [Full Text] [PDF]

				J. D. Fortenberry, M. L. Owens, and L. A. S. Brown S-nitrosoglutathione enhances neutrophil DNA fragmentation and cell death Am J Physiol Lung Cell Mol Physiol, March 1, 1999; 276(3): L435 - L442. [Abstract] [Full Text] [PDF]

				Y.-M. Kim, C. A. Bombeck, and T. R. Billiar Nitric Oxide as a Bifunctional Regulator of Apoptosis Circ. Res., February 19, 1999; 84(3): 253 - 256. [Full Text] [PDF]