Uncoupling Protein 2, in Vivo Distribution, Induction upon Oxidative Stress, and Evidence for Translational Regulation
Uncoupling protein 2 (UCP2) belongs to the mitochondrial anion carrier family and partially uncouples respiration from ATP synthesis when expressed in recombinant yeast mitochondria. We generated a highly sensitive polyclonal antibody against human UCP2. Its reactivity toward mitochondrial proteins was compared between wild type and ucp2(−/−) mice, leading to non-ambiguous identification of UCP2. We detected UCP2 in spleen, lung, stomach, and white adipose tissue. No UCP2 was detected in heart, skeletal muscle, liver, and brown adipose tissue. The level of UCP2 in spleen mitochondria is less than 1% of the level of UCP1 in brown adipose tissue mitochondria. Starvation and LPS treatments increase UCP2 level up to 12 times in lung and stomach, which supports the hypothesis that UCP2 responds to oxidative stress situations. Stimulation of the UCP2 expression occurs without any change in UCP2 mRNA levels. This is explained by translational regulation of the UCP2 mRNA. We have shown that an upstream open reading frame located in exon two of theucp2 gene strongly inhibits the expression of the protein. This further level of regulation of the ucp2 gene provides a mechanism by which expression can be strongly and rapidly induced under stress conditions. Uncoupling protein 2 (UCP2) belongs to the mitochondrial anion carrier family and partially uncouples respiration from ATP synthesis when expressed in recombinant yeast mitochondria. We generated a highly sensitive polyclonal antibody against human UCP2. Its reactivity toward mitochondrial proteins was compared between wild type and ucp2(−/−) mice, leading to non-ambiguous identification of UCP2. We detected UCP2 in spleen, lung, stomach, and white adipose tissue. No UCP2 was detected in heart, skeletal muscle, liver, and brown adipose tissue. The level of UCP2 in spleen mitochondria is less than 1% of the level of UCP1 in brown adipose tissue mitochondria. Starvation and LPS treatments increase UCP2 level up to 12 times in lung and stomach, which supports the hypothesis that UCP2 responds to oxidative stress situations. Stimulation of the UCP2 expression occurs without any change in UCP2 mRNA levels. This is explained by translational regulation of the UCP2 mRNA. We have shown that an upstream open reading frame located in exon two of theucp2 gene strongly inhibits the expression of the protein. This further level of regulation of the ucp2 gene provides a mechanism by which expression can be strongly and rapidly induced under stress conditions. uncoupling protein 1, 2, and 3 brain mitochondrial carrier protein brown adipose tissue gonadal white adipose tissue lipopolysaccharide Fos-choline 12 (N-dodecylphosphocholine) untranslated region open reading frame l-tosylamido-2-phenylethyl chloromethyl ketone 3-(cyclohexylamino)-1-propanesulfonic acid reactive oxygen species phosphate-buffered saline polymerase chain reaction N-hydroxysuccinimide UCP21 belongs to a large family of at least 35 anion carriers that are present in the inner mitochondrial membrane (1El Moualij B. Duyckaerts C. Lamotte-Brasseur J. Sluse F.E. Yeast. 1997; 13: 573-581Crossref PubMed Scopus (93) Google Scholar). Most of these carriers transport key metabolite substrates such as the malate, oxoglutarate, citrate, or products from the oxidative phosphorylation such as ADP3−, ATP4−, or Pi (for review see Ref. 2Kramer R. Palmieri F. Biochim. Biophys. Acta. 1989; 974: 1-23Crossref PubMed Scopus (112) Google Scholar). Since the discovery of ucp2 (3Gimeno R.E. Dembski M. Weng X. Deng N. Shyjan A.W. Gimeno C.J. Iris F. Ellis S.J. Woolf E.A. Tartaglia L.A. Diabetes. 1997; 46: 900-906Crossref PubMed Scopus (0) Google Scholar, 4Fleury C. Neverova M. Collins S. Raimbault S. Champigny O. Levi-Meyrueis C. Bouillaud F. Seldin M.F. Surwit R.S. Ricquier D. Warden C.H. Nat. Genet. 1997; 15: 269-272Crossref PubMed Scopus (1552) Google Scholar) and ucp3 (5Gong D.W. He Y. Karas M. Reitman M. J. Biol. Chem. 1997; 272: 24129-24132Abstract Full Text Full Text PDF PubMed Scopus (738) Google Scholar, 6Vidal-Puig A. Solanes G. Grujic D. Flier J.S. Lowell B.B. Biochem. Biophys. Res. Commun. 1997; 235: 79-82Crossref PubMed Scopus (681) Google Scholar, 7Boss O. Samec S. Paoloni-Giacobino A. Rossier C. Dulloo A. Seydoux J. Muzzin P. Giacobino J.P. FEBS Lett. 1997; 408: 39-42Crossref PubMed Scopus (996) Google Scholar) genes, a subfamily of mitochondrial carriers, related to the well known UCP1 from brown adipose tissue, has emerged in mammals as well as in plants (8Laloi M. Klein M. Riesmeier J.W. Muller-Rober B. Fleury C. Bouillaud F. Ricquier D. Nature. 1997; 389: 135-136Crossref PubMed Scopus (210) Google Scholar). The deduced coding sequence for UCP2 predicts 59% identity with UCP1, whereas the predicted UCP3 sequence is 72% identical to UCP2. The common characteristic of these proteins is to uncouple the respiratory chain from ATP synthesis by dissipating the proton electrochemical gradient when overexpressed in yeast mitochondria (for reviews see Refs. 9Boss O. Hagen T. Lowell B.B. Diabetes. 2000; 49: 143-156Crossref PubMed Scopus (389) Google Scholar and 10Ricquier D. Bouillaud F. Biochem. J. 2000; 345: 161-179Crossref PubMed Scopus (750) Google Scholar). They may also transport anions, like the other mitochondrial carriers, but these substrates are currently unknown. Over the last few years, several physiological roles have been proposed for UCP2, based on the expression of its mRNA upon various physiological conditions (for review see Ref. 11Fleury C. Sanchis D. Int. J. Biochem. Cell Biol. 1999; 31: 1261-1278Crossref PubMed Scopus (83) Google Scholar). Genetic studies suggested the novel UCPs might be linked to hyperinsulinemia (4Fleury C. Neverova M. Collins S. Raimbault S. Champigny O. Levi-Meyrueis C. Bouillaud F. Seldin M.F. Surwit R.S. Ricquier D. Warden C.H. Nat. Genet. 1997; 15: 269-272Crossref PubMed Scopus (1552) Google Scholar) or to the resting metabolic rate (12Bouchard C. Perusse L. Chagnon Y.C. Warden C. Ricquier D. Hum. Mol. Genet. 1997; 6: 1887-1889Crossref PubMed Scopus (229) Google Scholar) and consequently to the control of body weight. It was also proposed that UCP2 contributes to the inflammatory response and regulates the production of reactive oxygen species from mitochondria (13Lee F.Y. Li Y. Zhu H. Yang S. Lin H.Z. Trush M. Diehl A.M. Hepatology. 1999; 29: 677-687Crossref PubMed Scopus (144) Google Scholar, 14Negre-Salvayre A. Hirtz C. Carrera G. Cazenave R. Troly M. Salvayre R. Penicaud L. Casteilla L. FASEB. J. 1997; 11: 809-815Crossref PubMed Scopus (683) Google Scholar). Recently, it has been shown thatucp3(−/−) mice exhibited no consistent phenotypic abnormality, despite a reduced proton leak in muscle mitochondria and a higher level of intracellular ROS in muscle. Moreover, double knockoutucp1-ucp3 phenotype was indistinguishable from the singleucp1(−/−) phenotype (15Gong D.W. Monemdjou S. Gavrilova O. Leon L.R. Marcus-Samuels B. Chou C.J. Everett C. Kozak L.P. Li C. Deng C. Harper M.E. Reitman M.L. J. Biol. Chem. 2000; 275: 24129-24132Google Scholar, 16Vidal-Puig A.J. Grujic D. Zhang C.Y. Hagen T. Boss O. Ido Y. Szczepanik A. Wade J. Mootha V. Cortright R. Muoio D.M. Lowell B.B. J. Biol. Chem. 2000; 275: 16258-16266Abstract Full Text Full Text PDF PubMed Scopus (589) Google Scholar). One of the main problems encountered in the physiological studies of the new UCPs is the absence of reliable immunological tools to detect the proteins in vivo. More than 100 publications have described variation of UCP2 mRNA, whereas only seven analyses were performed at the protein level (for reviews see Refs. 9Boss O. Hagen T. Lowell B.B. Diabetes. 2000; 49: 143-156Crossref PubMed Scopus (389) Google Scholar and 10Ricquier D. Bouillaud F. Biochem. J. 2000; 345: 161-179Crossref PubMed Scopus (750) Google Scholar). In the present study, we have addressed this problem by generating antibodies against the complete human UCP2 sequence, rigorously evaluated their specificity and sensitivity, and compared them with commercial antibodies. Mitochondria were prepared either from ucp2(+/+) or ucp2(−/−) mice that were jointly created by the Ricquier and Collins laboratories (17Arsenijevic D. Onuma H. Pecqueur C. Raimbault S. Manning B.S. Miroux B. Goubern M. Alves-Guerra M. Couplan E. Surwit R. Bouillaud F. Richard D. Collins S. Ricquier D. Nat. Genet. 2000; 26: 435-439Crossref PubMed Scopus (935) Google Scholar). UCP2 protein was immunodetected without ambiguity in spleen, lung, stomach, and gonadal but in other UCP2 protein was in at a level in spleen, lung, stomach, and its expression was strongly upon and LPS in lung and of UCP2 mRNA and protein in that the of UCP2 is strongly by an upstream in the exon two of the and acid and antibodies were from and antibody were from and were from and were from antibody was from and and antibodies were from and antibody from mice were mice were generated on an and (17Arsenijevic D. Onuma H. Pecqueur C. Raimbault S. Manning B.S. Miroux B. Goubern M. Alves-Guerra M. Couplan E. Surwit R. Bouillaud F. Richard D. Collins S. Ricquier D. Nat. Genet. 2000; 26: 435-439Crossref PubMed Scopus (935) Google Scholar). mice were from and were to of with to or were with 100 of LPS from of of body mice were with the of were at times by of was in and for and the other was for the of mitochondria. The complete UCP2 was by the and and in a by The was by with the of the upstream at and were with the in with 2 and UCP2 was by and and and was of M. B. J. M. J. PubMed Scopus Google a expression related to the family J.W. PubMed Scopus Google Scholar). UCP1, human UCP2 and UCP3 were also a expression of M. a of that in frame with and of the of the UCP1 at was by the and and of UCP2 and UCP3 were by and as and and as They were the and of of UCP2 for was by and and and of expression of expression acid sequence to the of the recombinant and the sequence were on the were from tissue as described D. Bouillaud F. P. G. R. J. Penicaud L. J. Biol. Chem. Full Text PDF PubMed Google Scholar) or from with a of of tissue or of was as described A.M. Bouillaud F. E. Raimbault S. M. Ricquier D. J. Biochem. PubMed Scopus Google Scholar) an and the complete UCP2 as of UCP2 was with a and the was of the membrane with an of UCP2 and the UCP1, human UCP2, and UCP3 were as in the E. and as described B. J. Mol. Biol. PubMed Scopus Google Scholar). were to and in the of acid and the protein was to of or proteins were in and were the last was at and at and at of the at for was with to E. D. Scholar and by on as described B. Casteilla L. S. Raimbault S. S. Ricquier D. Bouillaud F. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The was in with were to the and for UCP2 mRNA and protein were at were in with the 2 and tissue or were in a at and were by of the at for The was at for and the mitochondrial was in of Mitochondria were to of of at and protein was by the acid to the were on a and membrane by for in a and was by the membrane with saline with for at antibodies were in and at The of the antibodies was to the to of the membrane with antibody was at in antibody was with the was for 1, and on were by a and was the from were compared on the of the UCP2 and the UCP1, human UCP2, and UCP3 were as in the E. B. J. Mol. Biol. PubMed Scopus Google Scholar). human UCP2 and acid proteins were on in the of and were two and the with UCP2 antibodies in this The an antibody that we against the UCP1 D. J.P. M. Biochem. J. PubMed Scopus Google toward This antibody detect only of UCP2 The and antibodies a and reactivity toward UCP2. the the antibody was the sensitive toward UCP2 and was times for UCP2 than either UCP1 or and antibodies we against the UCP2, and higher toward UCP2 than the other antibodies and specificity of UCP1, UCP2, and UCP3 in to of protein as antibodies were by was to to in of mitochondrial of protein by antibody of sequence was by the in to of protein as antibodies were by was to to in of mitochondrial of protein by antibody of sequence was by the in a new Since the we was the sensitive antibody and toward human or UCP2, it was to UCP2 in the of UCP2 protein in spleen, stomach, lung, and white adipose tissue this was the detected by the antibody in mitochondria mice we were to detect UCP2 in muscle, heart, liver, and brain mitochondria. other of in liver, and in brain mitochondria The in mitochondria to be UCP1 it in mitochondria from mice shown S. A. C. H. Harper M.E. Kozak L.P. Nature. 1997; PubMed Scopus Google UCP2 in mitochondria from mice theucp2 gene is in these mice shown S. A. C. H. Harper M.E. Kozak L.P. Nature. 1997; PubMed Scopus Google A. A. B. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google with and antibodies antibodies proteins than other antibodies in this any in and of them detected other proteins of weight. The antibody strongly toward proteins in and mitochondria 2 The a in spleen, liver, as a in The antibody with a protein in liver, and 2 of these in mitochondria from ucp2(−/−) mice, that these antibodies are to detect UCP2 in vivo. that UCP2 was and times less in lung and stomach, than in spleen mitochondria the of UCP2 protein expressed in we of the of antibody toward shown in of mitochondria the in than of spleen mitochondria. The was times with mitochondria from of the to the that the antibody toward mitochondria than spleen mitochondria Since the detected in to UCP1 and that the antibody was sensitive toward UCP2 than UCP1 we that UCP2 is less in spleen mitochondria than UCP1 is in of UCP2 in of UCP2 of UCP2 was as for UCP2 mRNA and protein levels. are expressed as of was the control 3 2 3 2 3 was as for UCP2 mRNA and protein levels. are expressed as of was the control in a new It has been that and LPS the level of UCP2 mRNA in skeletal muscle and O. Samec S. Dulloo A. Seydoux J. Muzzin P. Giacobino J.P. FEBS Lett. 1997; PubMed Scopus Google Scholar, R. J. A. C. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar, H. Yang Lin H.Z. S. G. Diehl A.M. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar, S. Sanchis D. B. Ricquier D. FEBS Lett. PubMed Scopus Google Scholar). mice were either with LPS with 100 of LPS or or for and several were for their UCP2 protein of UCP2 in muscle and in spleen but a increase of UCP2 protein was in and lung mitochondria and mice and two mice were and that UCP2 protein LPS only in lung mitochondria and its level 2 UCP2 protein to its expression level and No change in UCP2 protein was in the control mice with and in stomach, liver, heart, muscle, and spleen of of LPS that UCP2 protein in lung mitochondria the increase of UCP2 protein in lung mitochondria an increase of UCP2 protein of an of protein was also in mice LPS and mice were and for their UCP2 in lung mitochondria. UCP2 12 LPS This that LPS the synthesis of UCP2 protein in of UCP2 protein in lung mitochondria LPS Mitochondria from two or mice were prepared and LPS of UCP2 antibody at of of UCP2 protein open of UCP2 in lung mitochondria of was as were prepared from lung of control mice or The UCP2 was as UCP2 was of the membrane with the in the protein with gene were and UCP2 mRNA level was by UCP2 protein level was and times in lung and stomach, than in spleen UCP2 mRNA in were The between UCP2 protein and mRNA was in conditions. The of UCP2 mRNA in lung and upon and UCP2 mRNA also the LPS LPS UCP2 mRNA in spleen and lung were UCP2 protein in lung 12 times to times the level of UCP2 in spleen despite the of UCP2 protein that were in or the level of UCP2 mRNA with the of UCP2 protein. The between the of UCP2 mRNA and the of UCP2 protein detected in mitochondria as well as the between UCP2 mRNA and protein to expression was at the translational We have shown gene a open reading frame in exon 2 which a of C. A.M. Raimbault S. Miroux B. Fleury C. C. Bouillaud F. Ricquier D. Biochem. Biophys. Res. Commun. 1999; PubMed Scopus Google Scholar) the of UCP2 protein was by the in C. A.M. Raimbault S. Miroux B. Fleury C. C. Bouillaud F. Ricquier D. Biochem. Biophys. Res. Commun. 1999; PubMed Scopus Google we its the expression of UCP2 in were with the expression the complete sequence or the the The in were also to the of the recombinant UCP2 mRNA a higher than UCP2 mRNA UCP2 mRNA level was times higher in with than in spleen, the of UCP2 protein was only times higher in mitochondria than in spleen mitochondria and the between and of ucp2 gene is in spleen than in of with or the production of UCP2 protein and in without in UCP2 mRNA In the absence of UCP2 protein in mitochondria up to times the level of UCP2 in spleen the UCP2 mRNA level only times that the present in strongly inhibits the of UCP2 mRNA and supports the of between UCP2 mRNA and protein in of UCP2 expression in recombinant in of UCP2 in mitochondrial of UCP2 was as for UCP2 mRNA and protein levels. are expressed as of was are in 12 12 was as for UCP2 mRNA and protein levels. are expressed as of was are in in a new The region of known mitochondrial carriers was for the of upstream or the human and of them at least upstream or We and also and 3 by FEBS Lett. PubMed Scopus Google Scholar) were to translational of these mitochondrial that are a than a in their and a of by the between and In to their upstream the mitochondrial carriers that upstream at least two of the conditions described that are to translational regulation are expressed in carrier with an upstream were from the were the by A. A. of and was performed sequence of and was performed sequence of between and human C. A.M. Raimbault S. Miroux B. Fleury C. C. Bouillaud F. Ricquier D. Biochem. Biophys. Res. Commun. 1999; PubMed Scopus Google C. A.M. Raimbault S. Miroux B. Fleury C. C. Bouillaud F. Ricquier D. Biochem. Biophys. Res. Commun. 1999; PubMed Scopus Google H. PubMed Scopus Google G. A. Grujic D. Flier J.S. Lowell B.B. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google D. Fleury C. N. Goubern M. Neverova M. F. J. Raimbault S. Levi-Meyrueis C. Miroux B. Collins S. Seldin M. Richard D. Warden C. Bouillaud F. Ricquier D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google was from the human carrier ucp2 and protein 2 and brain mitochondrial carrier Sanchis and D. R. P. Mol. 1989; PubMed Scopus Google R. P. Mol. 1989; PubMed Scopus Google R.S. J. Biol. Chem. Full Text PDF PubMed Google were from the were the by A. A. of and was performed sequence was from the human carrier ucp2 and protein 2 and brain mitochondrial carrier D. Sanchis and D. in a new were to in UCP2 protein. antibodies Yang S. Lin H.Z. J. E. A. C.H. Diehl A.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Neverova M. Warden C.H. FASEB. J. PubMed Scopus Google Scholar, S. Zhu H. Li Y. Lin H. Trush Diehl A.M. Biochem. Biophys. 2000; PubMed Scopus Google antibodies against the UCP2 P. M. M. J. E. J. Gimeno R.E. Tartaglia L.A. FEBS Lett. 1999; 79-82Crossref PubMed Scopus Google or antibodies A. Hirtz C. Carrera G. Cazenave R. Troly M. Salvayre R. Penicaud L. Casteilla L. FASEB. 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FEBS Lett. 1999; 79-82Crossref PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar). are to the UCPs in of the antibodies with other This is in mitochondria antibodies in this detected and We also the UCP2 antibody that has been by Yang S. Lin H.Z. J. E. A. C.H. Diehl A.M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Zhu H. Li Y. Lin H. Trush Diehl A.M. Biochem. Biophys. 2000; PubMed Scopus Google Scholar). One was detected in mitochondria in and immunological that is of the expressed in that might have a than UCP2. antibody also a mitochondria from mice were to the vivo. we that UCP2 protein is expressed in spleen, lung, stomach, and mitochondria. the other UCP2 protein might be present at expressed only in of or UCP2 mRNA has a its is in the and the mRNA is in the and other D. R. Bouillaud F. Sanchis D. Champigny O. Ricquier D. J. PubMed Scopus Google Scholar). of the that UCP2 mRNA with the variation of the protein. UCP2 protein is times less expressed in mitochondria than in spleen the of UCP2 mRNA in is the increase of UCP2 protein in lung and upon or LPS is by an increase of UCP2 mRNA. of in ucp2 gene times the expression of UCP2 protein in without any at the mRNA of with a and the expression of the UCP2 and of the or the of the upstream also the expression of UCP2 the ucp2 gene is at translational level by an upstream regulation of the ucp2 UCP2 mRNA is highly expressed in spleen, lung, stomach, and but is expressed in the other Since UCP2 protein was only in the its mRNA was highly it is that the tissue specificity of ucp2 gene expression is partially at the whereas the level of UCP2 protein is by translational The mechanism by which UCP2 protein synthesis is exon and the LPS an of UCP2 exon 2 the increase of UCP2 protein in lung it is that of the the at the and only few of them the at the UCP2 It is that UCPs also upstream Since a between mRNA and protein expression has been also suggested for UCP3 by 1999; PubMed Scopus Google be mRNA of UCP2, or S. Samec S. Seydoux J. N. Dulloo FEBS Lett. 1999; PubMed Scopus Google Scholar) and A. A. B. J. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) studies on muscle mitochondria and mitochondria from mice, They that ucp2 gene was strongly mitochondrial proton In UCP2 protein in the of the translational regulation of ucp2 it is that UCP2 mRNA the expression of the protein It is that UCP1 is a proton highly expressed in brown adipose tissue mitochondria. In UCP1 protein up to of mitochondrial proteins D. G. Bouillaud F. J. J. FEBS Lett. PubMed Scopus Google and its on its and its by LPS UCP2 protein in lung but only of the mitochondrial that either proteins the or have the UCP2 and UCP3 are by M. M. Gimeno R.E. Dembski M. P. Zhang M. P. Tartaglia L.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, T. E. M. M. FEBS Lett. 1999; PubMed Scopus Google Scholar, E. M. Fleury C. S. Sanchis D. J. Ricquier D. Goubern M. Bouillaud F. J. 1999; PubMed Scopus Google it is that UCP2 is in whereas UCP1 is by in mitochondria. the other also that the of the new UCPs is to by a mitochondrial A. Hirtz C. Carrera G. Cazenave R. Troly M. Salvayre R. Penicaud L. Casteilla L. FASEB. J. 1997; 11: 809-815Crossref PubMed Scopus (683) Google (13Lee F.Y. Li Y. Zhu H. Yang S. Lin H.Z. Trush M. Diehl A.M. Hepatology. 1999; 29: 677-687Crossref PubMed Scopus (144) Google and Yang S. Zhu H. Li Y. Lin H. Trush Diehl A.M. Biochem. Biophys. 2000; PubMed Scopus Google Scholar) have proposed that UCP2 regulates the production of reactive oxygen species by uncoupling the respiratory as suggested by Biochim. Biophys. Acta. PubMed Scopus Google Scholar). In studies on mice A.J. Grujic D. Zhang C.Y. Hagen T. Boss O. Ido Y. Szczepanik A. Wade J. Mootha V. Cortright R. Muoio D.M. Lowell B.B. J. Biol. Chem. 2000; 275: 16258-16266Abstract Full Text Full Text PDF PubMed Scopus (589) Google Scholar) mice (17Arsenijevic D. Onuma H. Pecqueur C. Raimbault S. Manning B.S. Miroux B. Goubern M. Alves-Guerra M. Couplan E. Surwit R. Bouillaud F. Richard D. Collins S. Ricquier D. Nat. Genet. 2000; 26: 435-439Crossref PubMed Scopus (935) Google Scholar) that proteins the production of ROS higher of ROS were in muscle and The that UCP2 is in lung and upon LPS and also this The of of UCP2 protein LPS is consistent with a response leading to an oxidative in of by LPS the production of such as J. In Cell Biol. 1997; Scopus Google Scholar) which the The of reduced and the level of intracellular ROS (for review see Ref. J. PubMed Scopus Google Scholar). Since has also been shown to a of reduced level in lung J. PubMed Scopus Google Scholar) and in B. A. S. Res. PubMed Scopus Google that UCP2 have any in conditions but is when the level of intracellular reactive oxygen species is In this translational regulation of UCP2 might a based on the large of UCP2 mRNA the lung and the as two UCP2 an Since are to and the of UCP2 might be to the from oxidative by or We are to Onuma for in the ucp2(−/−) L. P. Kozak for the of M. and J. E. for the expression D. Sanchis for the of UCP3 M. and A. for and for reading of the