Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production

被引:918
作者
Arsenijevic, D
Onuma, H
Pecqueur, C
Raimbault, S
Manning, BS
Miroux, B
Couplan, E
Alves-Guerra, MC
Goubern, M
Surwit, R
Bouillaud, F
Richard, D
Collins, S
Ricquier, D [1 ]
机构
[1] Ctr Rech Endocrinol Mol & Dev, CNRS, UPR 9078, Meudon, France
[2] INRA, Ecole Prat Hautes Etud, Jouy En Josas, France
[3] Duke Univ, Med Ctr, Durham, NC USA
[4] Univ Laval, Ctr Rech Metab Energet, Quebec City, PQ, Canada
[5] Hop Laval, Ctr Rech, Quebec City, PQ, Canada
基金
美国国家卫生研究院;
关键词
D O I
10.1038/82565
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1-3). As Ucp2 is widely expressed in mammalian tissues(4,5), uncouples respiration(6) and resides within a region of genetic linkage to obesity(4), a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages(4,5,7), suggesting a role for Ucp2 In immunity or inflammatory responsiveness(4). We investigated the response to infection with Toxoplasma gondii in Ucp2(-/-) mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2(-/-) mice (63% decrease, P<0.04). Macrophages from Ucp2(-/-) mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.
引用
收藏
页码:435 / 439
页数:5
相关论文
共 28 条
[1]  
AKINSHINA G T, 1975, Byulleten' Eksperimental'noi Biologii i Meditsiny, V80, P60
[2]   Altered energy balance and cytokine gene expression in a murine model of chronic infection with Toxoplasma gondii [J].
Arsenijevic, D ;
Girardier, L ;
Seydoux, J ;
Chang, HR ;
Dulloo, AG .
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, 1997, 272 (05) :E908-E917
[3]   Uncoupling proteins 2 and 3 - Potential regulators of mitochondrial energy metabolism [J].
Boss, O ;
Hagen, T ;
Lowell, BB .
DIABETES, 2000, 49 (02) :143-156
[4]  
Cohen RD, 1999, INFLAMM BOWEL DIS, V5, P1
[5]   Mitochondrial uncoupling:: Role of uncoupling protein anion carriers and relationship to thermogenesis and weight control "The benefits of losing control" [J].
Diehl, AM ;
Hoek, JB .
JOURNAL OF BIOENERGETICS AND BIOMEMBRANES, 1999, 31 (05) :493-506
[6]   Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese [J].
Enerback, S ;
Jacobsson, A ;
Simpson, EM ;
Guerra, C ;
Yamashita, H ;
Harper, ME ;
Kozak, LP .
NATURE, 1997, 387 (6628) :90-94
[7]   Uncoupling protein-2: A novel gene linked to obesity and hyperinsulinemia [J].
Fleury, C ;
Neverova, M ;
Collins, S ;
Raimbault, S ;
Champigny, O ;
LeviMeyrueis, C ;
Bouillaud, F ;
Seldin, MF ;
Surwit, RS ;
Ricquier, D ;
Warden, CH .
NATURE GENETICS, 1997, 15 (03) :269-272
[8]   Cloning and characterization of an uncoupling protein homolog - A potential molecular mediator of human thermogenesis [J].
Gimeno, RE ;
Dembski, M ;
Weng, X ;
Deng, NH ;
Shyjan, AW ;
Gimeno, CJ ;
Iris, F ;
Ellis, SJ ;
Woolf, EA ;
Tartaglia, LA .
DIABETES, 1997, 46 (05) :900-906
[9]   A plant cold-induced uncoupling protein [J].
Laloi, M ;
Klein, M ;
Riesmeier, JW ;
MullerRober, B ;
Fleury, C ;
Bouillaud, F ;
Ricquier, D .
NATURE, 1997, 389 (6647) :135-136
[10]   Kupffer cells are a dominant site of uncoupling protein 2 expression in rat liver [J].
Larrouy, D ;
Laharrague, P ;
Carrera, G ;
ViguerieBascands, N ;
LeviMeyrueis, C ;
Fleury, C ;
Pecqueur, C ;
Nibbelink, M ;
Andre, M ;
Casteilla, L ;
Ricquier, D .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 235 (03) :760-764