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

J. Biol. Chem., Vol. 280, Issue 19, 19062-19069, May 13, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/19/19062    most recent M500566200v1 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 Bai, Y. Articles by Collins, S. Search for Related Content PubMed PubMed Citation Articles by Bai, Y. Articles by Collins, S. Social Bookmarking                      What's this?

Persistent Nuclear Factor-B Activation in Ucp2-/- Mice Leads to Enhanced Nitric Oxide and Inflammatory Cytokine Production^*

Yushi Bai, Hiroki Onuma, Xu Bai, Alexander V. Medvedev, Mary Misukonis¶, J. Brice Weinberg¶, Wenhong Cao, Jacques Robidoux, Lisa M. Floering, Kiefer W. Daniel, and Sheila Collins||

From the Division of Biological Sciences, Endocrine Biology Program, CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709-2137 and Department of Psychiatry and Behavioral Sciences and ^¶Division of Hematology-Oncology, Veterans Administration Medical Center/Duke University Medical Center, Durham, North Carolina 27710

One of the phenotypes of mice with targeted disruption of the uncoupling protein-2 gene (Ucp2-/-) is greater macrophage phagocytic activity and free radical production, resulting in a striking resistance to infectious microorganisms. In this study, the molecular mechanisms of this enhanced immune response were investigated. We found that levels of nitric oxide measured in either plasma or isolated macrophages from Ucp2-/- mice are significantly elevated in response to bacterial lipopolysaccharide challenge compared with similarly treated Ucp2+/+ mice. Likewise, expression of inducible nitric-oxide synthase and inflammatory cytokines is higher in Ucp2-/- mice in vivo and in vitro. Key steps in the activation cascade of nuclear factor (NF)-B, including IB kinase and nuclear translocation of NF-B subunits, are all remarkably enhanced in Ucp2-/- mice, most notably even under basal conditions. The elevated basal activity of IB kinase in macrophages from Ucp2-/- mice can be blocked by cell-permeable inhibitors of superoxide and hydrogen peroxide generation, but not by a specific inhibitor for inducible nitric-oxide synthase. Isolated mitochondria from Ucp2-/- cells produced more superoxide/hydrogen peroxide. We conclude that mitochrondrially derived reactive oxygen from Ucp2-/- cells constitutively activates NF-B, resulting in a "primed" state to both potentiate and amplify the inflammatory response upon subsequent stimulation.

Received for publication, January 18, 2005 , and in revised form, February 28, 2005.

^* This work was supported by National Institutes of Health Award R01-DK54024 (to S. C.) and a Research Award from the American Diabetes Association (to S. C.). 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.

^|| To whom correspondence should be addressed: Endocrine Biology Program, CIIT Centers for Health Research, 6 Davis Dr., P. O. Box 12137, Research Triangle Park, NC 27709-2137. Tel.: 919-558-1378; Fax: 919-558-1305; E-mail: scollins{at}ciit.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Pi, Y. Bai, K. W. Daniel, D. Liu, O. Lyght, D. Edelstein, M. Brownlee, B. E. Corkey, and S. Collins Persistent Oxidative Stress Due to Absence of Uncoupling Protein 2 Associated with Impaired Pancreatic {beta}-Cell Function Endocrinology, July 1, 2009; 150(7): 3040 - 3048. [Abstract] [Full Text] [PDF]

				F. Moukdar, J. Robidoux, O. Lyght, J. Pi, K. W. Daniel, and S. Collins Reduced antioxidant capacity and diet-induced atherosclerosis in uncoupling protein-2-deficient mice J. Lipid Res., January 1, 2009; 50(1): 59 - 70. [Abstract] [Full Text] [PDF]

				A. Elorza, B. Hyde, H. K. Mikkola, S. Collins, and O. S. Shirihai UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis J. Biol. Chem., November 7, 2008; 283(45): 30461 - 30470. [Abstract] [Full Text] [PDF]

				J. Diao, E. M. Allister, V. Koshkin, S. C. Lee, A. Bhattacharjee, C. Tang, A. Giacca, C. B. Chan, and M. B. Wheeler UCP2 is highly expressed in pancreatic {alpha}-cells and influences secretion and survival PNAS, August 19, 2008; 105(33): 12057 - 12062. [Abstract] [Full Text] [PDF]

				C. Pecqueur, T. Bui, C. Gelly, J. Hauchard, C. Barbot, F. Bouillaud, D. Ricquier, B. Miroux, and C. B. Thompson Uncoupling protein-2 controls proliferation by promoting fatty acid oxidation and limiting glycolysis-derived pyruvate utilization FASEB J, January 1, 2008; 22(1): 9 - 18. [Abstract] [Full Text] [PDF]

				Y. Emre, C. Hurtaud, M. Karaca, T. Nubel, F. Zavala, and D. Ricquier Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes PNAS, November 27, 2007; 104(48): 19085 - 19090. [Abstract] [Full Text] [PDF]

				Q. F. Collins, H.-Y. Liu, J. Pi, Z. Liu, M. J. Quon, and W. Cao Epigallocatechin-3-gallate (EGCG), A Green Tea Polyphenol, Suppresses Hepatic Gluconeogenesis through 5'-AMP-activated Protein Kinase J. Biol. Chem., October 12, 2007; 282(41): 30143 - 30149. [Abstract] [Full Text] [PDF]

				T. Feldkamp, A. Kribben, N. F. Roeser, T. Ostrowski, and J. M. Weinberg Alleviation of fatty acid and hypoxia-reoxygenation-induced proximal tubule deenergization by ADP/ATP carrier inhibition and glutamate Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1606 - F1616. [Abstract] [Full Text] [PDF]

				E. Chevillotte, M. Giralt, B. Miroux, D. Ricquier, and F. Villarroya Uncoupling Protein-2 Controls Adiponectin Gene Expression in Adipose Tissue Through the Modulation of Reactive Oxygen Species Production Diabetes, April 1, 2007; 56(4): 1042 - 1050. [Abstract] [Full Text] [PDF]

				Z. Derdak, P. Fulop, E. Sabo, R. Tavares, E. P. Berthiaume, M. B. Resnick, G. Paragh, J. R. Wands, and G. Baffy Enhanced colon tumor induction in uncoupling protein-2 deficient mice is associated with NF-{kappa}B activation and oxidative stress Carcinogenesis, May 1, 2006; 27(5): 956 - 961. [Abstract] [Full Text] [PDF]

				S. Vogler, J. Pahnke, S. Rousset, D. Ricquier, H. Moch, B. Miroux, and S. M. Ibrahim Uncoupling Protein 2 Has Protective Function during Experimental Autoimmune Encephalomyelitis Am. J. Pathol., May 1, 2006; 168(5): 1570 - 1575. [Abstract] [Full Text] [PDF]