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

This Article Full Text Full Text (PDF) 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 Bellocq, A. Articles by Baud, L. Search for Related Content PubMed PubMed Citation Articles by Bellocq, A. Articles by Baud, L. Social Bookmarking                      What's this?

J Biol Chem, Vol. 273, Issue 9, 5086-5092, February 27, 1998

Low Environmental pH Is Responsible for the Induction of Nitric-oxide Synthase in Macrophages
EVIDENCE FOR INVOLVEMENT OF NUCLEAR FACTOR-B ACTIVATION

Agnès Bellocq, Sidonie Suberville, Carole Philippe, France Bertrand^§, Joëlle Perez, Bruno Fouqueray, Gisèle Cherqui^§, and Laurent Baud

From the  INSERM U. 64, Hôpital Tenon, 75020 Paris and ^§ INSERM U. 402, Hôpital Saint-Antoine, 75012 Paris, France

Stimulation of macrophages with endotoxin and/or cytokines is responsible for the expression of the inducible isoform of nitric oxide synthase (iNOS). Because macrophages are exposed to low pH within the microenvironment of inflammatory lesions, the potential role of acidic pH as an additional regulator of iNOS was investigated. Substitution of the culture medium of rat peritoneal macrophages at pH 7.4 with medium at pH 7.0 up-regulated iNOS activity, as reflected by a 2.5-fold increase in nitrite accumulation. The increase in iNOS activity was associated with a similar increase in iNOS mRNA expression that reflected an increase in iNOS mRNA synthesis rather than stability. Low environmental pH-induced iNOS gene transcription involved the activation of nuclear factor-B (NF-B) transcription factor since exposure of macrophages to low environmental pH both increased NF-B binding activity in the nucleus and enhanced NF-B-driven reporter gene expression. In addition, treatment of macrophages with pyrrolidine dithiocarbamate or n-acetyl-leucinyl-leucinyl-norleucinal, two drugs preventing NF-B translocation to the nucleus, canceled low pH-induced nitrite accumulation. The overall mechanism required the synthesis of tumor necrosis factor  (TNF). Indeed, 1) elevated TNF bioactivity was observed in the medium of macrophages exposed to pH 7.0, and 2) incubation of macrophages with a neutralizing anti-TNF antibody impaired both NF-B activation and nitrite accumulation in response to acid challenge. In summary, exposure of macrophages to acidic microenvironment in inflammatory lesions leads to the up-regulation of iNOS activity through the activation of NF-B.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				P. Ponnuswamy, E. Ostermeier, A. Schrottle, J. Chen, P. L. Huang, G. Ertl, B. Nieswandt, and P. J. Kuhlencordt Oxidative Stress and Compartment of Gene Expression Determine Proatherosclerotic Effects of Inducible Nitric Oxide Synthase Am. J. Pathol., June 1, 2009; 174(6): 2400 - 2410. [Abstract] [Full Text] [PDF]

				J. A. Kellum, M. Song, and E. Almasri Hyperchloremic acidosis increases circulating inflammatory molecules in experimental sepsis. Chest, October 1, 2006; 130(4): 962 - 967. [Abstract] [Full Text] [PDF]

				C. Lewis and C. Murdoch Macrophage Responses to Hypoxia: Implications for Tumor Progression and Anti-Cancer Therapies Am. J. Pathol., September 1, 2005; 167(3): 627 - 635. [Abstract] [Full Text] [PDF]

				C. J. Lang, P. Dong, E. K. Hosszu, and I. R. Doyle Effect of CO2 on LPS-induced cytokine responses in rat alveolar macrophages Am J Physiol Lung Cell Mol Physiol, July 1, 2005; 289(1): L96 - L103. [Abstract] [Full Text] [PDF]

				H. Christou, N. Bailey, M. S. Kluger, S. A. Mitsialis, and S. Kourembanas Extracellular acidosis induces heme oxygenase-1 expression in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2647 - H2652. [Abstract] [Full Text] [PDF]

				G. Regis, M. Bosticardo, L. Conti, S. De Angelis, D. Boselli, B. Tomaino, P. Bernabei, M. Giovarelli, and F. Novelli Iron regulates T-lymphocyte sensitivity to the IFN-{gamma}/STAT1 signaling pathway in vitro and in vivo Blood, April 15, 2005; 105(8): 3214 - 3221. [Abstract] [Full Text] [PDF]

				Y. Kato, C. A. Lambert, A. C. Colige, P. Mineur, A. Noel, F. Frankenne, J.-M. Foidart, M. Baba, R.-I. Hata, K. Miyazaki, et al. Acidic Extracellular pH Induces Matrix Metalloproteinase-9 Expression in Mouse Metastatic Melanoma Cells through the Phospholipase D-Mitogen-activated Protein Kinase Signaling J. Biol. Chem., March 25, 2005; 280(12): 10938 - 10944. [Abstract] [Full Text] [PDF]

				J. D. Lang, M. Figueroa, K. D. Sanders, M. Aslan, Y. Liu, P. Chumley, and B. A. Freeman Hypercapnia via Reduced Rate and Tidal Volume Contributes to Lipopolysaccharide-induced Lung Injury Am. J. Respir. Crit. Care Med., January 15, 2005; 171(2): 147 - 157. [Abstract] [Full Text] [PDF]

				H. A. Franch, S. Raissi, X. Wang, B. Zheng, J. L. Bailey, and S. R. Price Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: consequences on proteolysis Am J Physiol Renal Physiol, October 1, 2004; 287(4): F700 - F706. [Abstract] [Full Text] [PDF]

				A. Cheron, J. Peltier, J. Perez, A. Bellocq, B. Fouqueray, and L. Baud 15-Deoxy-{Delta}12,14-Prostaglandin J2 Inhibits Glucocorticoid Binding and Signaling in Macrophages through a Peroxisome Proliferator-Activated Receptor {gamma}-Independent Process J. Immunol., June 15, 2004; 172(12): 7677 - 7683. [Abstract] [Full Text] [PDF]

				J. A. Kellum, M. Song, and J. Li Lactic and hydrochloric acids induce different patterns of inflammatory response in LPS-stimulated RAW 264.7 cells Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2004; 286(4): R686 - R692. [Abstract] [Full Text] [PDF]

				J. A. Kellum, M. Song, and R. Venkataraman Effects of Hyperchloremic Acidosis on Arterial Pressure and Circulating Inflammatory Molecules in Experimental Sepsis Chest, January 1, 2004; 125(1): 243 - 248. [Abstract] [Full Text] [PDF]

				G. Fritsche, M. Dlaska, H. Barton, I. Theurl, K. Garimorth, and G. Weiss Nramp1 Functionality Increases Inducible Nitric Oxide Synthase Transcription Via Stimulation of IFN Regulatory Factor 1 Expression J. Immunol., August 15, 2003; 171(4): 1994 - 1998. [Abstract] [Full Text] [PDF]

				K. Takeshita, Y. Suzuki, K. Nishio, O. Takeuchi, K. Toda, H. Kudo, N. Miyao, M. Ishii, N. Sato, K. Naoki, et al. Hypercapnic Acidosis Attenuates Endotoxin-Induced Nuclear Factor-{kappa}B Activation Am. J. Respir. Cell Mol. Biol., July 1, 2003; 29(1): 124 - 132. [Abstract] [Full Text] [PDF]

				D. Fukumura, L. Xu, Y. Chen, T. Gohongi, B. Seed, and R. K. Jain Hypoxia and Acidosis Independently Up-Regulate Vascular Endothelial Growth Factor Transcription in Brain Tumors in Vivo Cancer Res., August 1, 2001; 61(16): 6020 - 6024. [Abstract] [Full Text] [PDF]

				S. A. KHARITONOV and P. J. BARNES Exhaled Markers of Pulmonary Disease Am. J. Respir. Crit. Care Med., June 1, 2001; 163(7): 1693 - 1722. [Full Text] [PDF]

				J.-F. Pittet, L. N. Lu, D. G. Morris, K. Modelska, W. J. Welch, H. V. Carey, J. Roux, and M. A. Matthay Reactive Nitrogen Species Inhibit Alveolar Epithelial Fluid Transport After Hemorrhagic Shock in Rats J. Immunol., May 15, 2001; 166(10): 6301 - 6310. [Abstract] [Full Text] [PDF]

				U. Ponnappan and L. S. F. Soderberg Inflammatory macrophage nuclear factor-{kappa}B and proteasome activity are inhibited following exposure to inhaled isobutyl nitrite J. Leukoc. Biol., April 1, 2001; 69(4): 639 - 644. [Abstract] [Full Text]

				V. Couloigner, M. Teixeira, P. Hulin, O. Sterkers, M. Bichara, B. Escoubet, G. Planelles, and E. Ferrary Effect of locally applied drugs on the pH of luminal fluid in the endolymphatic sac of guinea pig Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2000; 279(5): R1695 - R1700. [Abstract] [Full Text] [PDF]

				L. Xu and I. J. Fidler Acidic pH-induced Elevation in Interleukin 8 Expression by Human Ovarian Carcinoma Cells Cancer Res., August 1, 2000; 60(16): 4610 - 4616. [Abstract] [Full Text]

				A. Bellocq, S. Doublier, S. Suberville, J. Perez, B. Escoubet, B. Fouqueray, D. R. Puyol, and L. Baud Somatostatin Increases Glucocorticoid Binding and Signaling in Macrophages by Blocking the Calpain-specific Cleavage of Hsp 90 J. Biol. Chem., December 24, 1999; 274(52): 36891 - 36896. [Abstract] [Full Text] [PDF]

				Q. Shi, J. L. Abbruzzese, S. Huang, I. J. Fidler, Q. Xiong, and K. Xie Constitutive and Inducible Interleukin 8 Expression by Hypoxia and Acidosis Renders Human Pancreatic Cancer Cells More Tumorigenic and Metastatic Clin. Cancer Res., November 1, 1999; 5(11): 3711 - 3721. [Abstract] [Full Text] [PDF]

				A. Nicoletti and J.-B. Michel Cardiac fibrosis and inflammation: interaction with hemodynamic and hormonal factors Cardiovasc Res, March 1, 1999; 41(3): 532 - 543. [Abstract] [Full Text] [PDF]

				W. S. Cruz, J. A. Corbett, W. J. Longmore, and M. A. Moxley Nitric oxide participates in early events associated with NNMU-induced acute lung injury in rats Am J Physiol Lung Cell Mol Physiol, February 1, 1999; 276(2): L263 - L268. [Abstract] [Full Text] [PDF]

				J. Du, W. E. Mitch, X. Wang, and S. R. Price Glucocorticoids Induce Proteasome C3 Subunit Expression in L6 Muscle Cells by Opposing the Suppression of Its Transcription by NF-kappa B J. Biol. Chem., June 23, 2000; 275(26): 19661 - 19666. [Abstract] [Full Text] [PDF]