This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tendler, D. S. Articles by Lowenstein, C. J. Search for Related Content PubMed PubMed Citation Articles by Tendler, D. S. Articles by Lowenstein, C. J.

Intersection of Interferon and Hypoxia Signal Transduction Pathways in Nitric Oxide-induced Tumor Apoptosis¹

Division of Cardiology, Department of Medicine [D. S. T., C. B., C. J. L.], and Departments of Oncology [T. W., D. A. P.], and Dermatology [E. A. R.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and Division of Hematology and Oncology [E. L. H.], Brigham and Women‘s Hospital, Boston, Massachusetts 02115

Activated macrophages play a central role in antitumor immunity. However, the stimuli that activate macrophages to kill tumor cells are not completely understood. Because the center of solid tumors can be hypoxic, we hypothesized that hypoxia may be an important signal in activating macrophages to kill tumor cells. Hypoxia stimulates IFN-primed macrophages to express the inducible nitric oxide synthase (NOS2) and to synthesize nitric oxide (NO). We show that this synergy between IFN and hypoxia is mediated by the direct interaction of the hypoxia inducible factor-1 (HIF-1) and IFN regulatory factor-1 (IRF-1), which are both required for the hypoxic transcription of NOS2. This interaction between HIF-1 and IRF-1 may explain the mechanism by which macrophages infiltrating into tumors are activated to express NOS2 and to produce NO, a mediator of tumor apoptosis.

This article has been cited by other articles:

				M. Kido, L. Du, C. C. Sullivan, X. Li, R. Deutsch, S. W. Jamieson, and P. A. Thistlethwaite Hypoxia-Inducible Factor 1-Alpha Reduces Infarction and Attenuates Progression of Cardiac Dysfunction After Myocardial Infarction in the Mouse J. Am. Coll. Cardiol., December 6, 2005; 46(11): 2116 - 2124. [Abstract] [Full Text] [PDF]

				C. L. Galindo, A. A. Fadl, J. Sha, and A. K. Chopra Microarray Analysis of Aeromonas hydrophila Cytotoxic Enterotoxin-Treated Murine Primary Macrophages Infect. Immun., September 1, 2004; 72(9): 5439 - 5445. [Abstract] [Full Text] [PDF]

				J.-I Chao, P.-C. Kuo, and T.-S. Hsu Down-regulation of Survivin in Nitric Oxide-induced Cell Growth Inhibition and Apoptosis of the Human Lung Carcinoma Cells J. Biol. Chem., May 7, 2004; 279(19): 20267 - 20276. [Abstract] [Full Text] [PDF]

				Y. Hoshiya, V. Gupta, H. Kawakubo, E. Brachtel, J. L. Carey, L. Sasur, A. Scott, P. K. Donahoe, and S. Maheswaran Mullerian Inhibiting Substance Promotes Interferon {gamma}-induced Gene Expression and Apoptosis in Breast Cancer Cells J. Biol. Chem., December 19, 2003; 278(51): 51703 - 51712. [Abstract] [Full Text] [PDF]

				S. Daniliuc, H. Bitterman, M. A. Rahat, A. Kinarty, D. Rosenzweig, and L. Nitza Hypoxia Inactivates Inducible Nitric Oxide Synthase in Mouse Macrophages by Disrupting Its Interaction with {alpha}-Actinin 4 J. Immunol., September 15, 2003; 171(6): 3225 - 3232. [Abstract] [Full Text] [PDF]

				M. Ramanathan, A. Giladi, and S. J. Leibovich Regulation of Vascular Endothelial Growth Factor Gene Expression in Murine Macrophages by Nitric Oxide and Hypoxia Experimental Biology and Medicine, June 1, 2003; 228(6): 697 - 705. [Abstract] [Full Text] [PDF]

				A. Alfranca, M. D. Gutierrez, A. Vara, J. Aragones, F. Vidal, and M. O. Landazuri c-Jun and Hypoxia-Inducible Factor 1 Functionally Cooperate in Hypoxia-Induced Gene Transcription Mol. Cell. Biol., January 1, 2002; 22(1): 12 - 22. [Abstract] [Full Text] [PDF]

				B. R. Pitt and C. M. St. Croix Complex Regulation of iNOS in Lung Am. J. Respir. Cell Mol. Biol., January 1, 2002; 26(1): 6 - 9. [Full Text] [PDF]