Key points are not available for this paper at this time.
Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and its component phospholipid, 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine, induce endothelial cells (EC) to synthesize chemotactic factors, such as interleukin 8 (IL-8). Previously, we demonstrated a role for c-Src kinase activation in Ox-PAPC-induced IL-8 transcription. In this study, we have examined the mechanism regulating IL-8 transcription by Ox-PAPC downstream of c-Src. Our findings demonstrate an important role for JAK2 in the regulation of IL-8 transcription by Ox-PAPC. Treatment of human aortic EC with Ox-PAPC and 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine induced a rapid yet sustained activation of JAK2; activation of JAK2 by Ox-PAPC was dependent on c-Src kinase activity. Furthermore, pretreatment with selective JAK2 inhibitors significantly reduced Ox-PAPC-induced IL-8 transcription. In previous studies, we also demonstrated activation of STAT3 by Ox-PAPC. Here we provide evidence that STAT3 activation by Ox-PAPC is dependent on JAK2 activation and that STAT3 activation regulates IL-8 transcription by Ox-PAPC in human EC. Transfection with small interfering RNA against STAT3 significantly reduced Ox-PAPC-induced IL-8 transcription. Using chromatin immunoprecipitation assays, we demonstrated binding of activated STAT3 to the sequence flanking the consensus γ-interferon activation sequence (GAS) in the IL-8 promoter; site-directed mutagenesis of GAS inhibited IL-8 transcription by Ox-PAPC. Finally, these studies demonstrate a role for STAT3 activation in atherosclerosis in vivo. We found increased staining for activated STAT3 in the inflammatory regions of human atherosclerotic lesions and reduced fatty streak formation in EC-specific STAT3 knock-out mice on the atherogenic diet. Taken together, these data demonstrate an important role for the JAK2/STAT3 pathway in Ox-PAPC-induced IL-8 transcription in vitro and in atherosclerosis in vivo. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and its component phospholipid, 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine, induce endothelial cells (EC) to synthesize chemotactic factors, such as interleukin 8 (IL-8). Previously, we demonstrated a role for c-Src kinase activation in Ox-PAPC-induced IL-8 transcription. In this study, we have examined the mechanism regulating IL-8 transcription by Ox-PAPC downstream of c-Src. Our findings demonstrate an important role for JAK2 in the regulation of IL-8 transcription by Ox-PAPC. Treatment of human aortic EC with Ox-PAPC and 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine induced a rapid yet sustained activation of JAK2; activation of JAK2 by Ox-PAPC was dependent on c-Src kinase activity. Furthermore, pretreatment with selective JAK2 inhibitors significantly reduced Ox-PAPC-induced IL-8 transcription. In previous studies, we also demonstrated activation of STAT3 by Ox-PAPC. Here we provide evidence that STAT3 activation by Ox-PAPC is dependent on JAK2 activation and that STAT3 activation regulates IL-8 transcription by Ox-PAPC in human EC. Transfection with small interfering RNA against STAT3 significantly reduced Ox-PAPC-induced IL-8 transcription. Using chromatin immunoprecipitation assays, we demonstrated binding of activated STAT3 to the sequence flanking the consensus γ-interferon activation sequence (GAS) in the IL-8 promoter; site-directed mutagenesis of GAS inhibited IL-8 transcription by Ox-PAPC. Finally, these studies demonstrate a role for STAT3 activation in atherosclerosis in vivo. We found increased staining for activated STAT3 in the inflammatory regions of human atherosclerotic lesions and reduced fatty streak formation in EC-specific STAT3 knock-out mice on the atherogenic diet. Taken together, these data demonstrate an important role for the JAK2/STAT3 pathway in Ox-PAPC-induced IL-8 transcription in vitro and in atherosclerosis in vivo. Cardiovascular disease (CVD) 2The abbreviations used are: CVD, endothelial cell; siRNA, small interfering RNA; ChIP, chromatin immunoprecipitation; GAS, γ-interferon activation sequence; Ox-PAPC, oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; PEIPC, 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine; HAEC, human aortic endothelial cells; IFN, interferon; IL, interleukin; STAT, signal transducers and activators of transcription; ELISA, enzyme-linked immunosorbent assay; qRT, quantitative real time; HMEC, human microvascular endothelial cells. is a major cause of morbidity and mortality in Western nations. It is estimated that 80 million Americans have one or more forms of CVD. Atherosclerosis, a common cause of CVD, is a chronic inflammatory condition, involving enhanced monocyte/endothelial cell interactions. Clinical studies suggest that the inflammatory index, as measured by levels of C-reactive protein or myeloperoxidase activity, is an important independent predictor of the risk of atherosclerosis. Our laboratory has demonstrated that oxidation products of palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC) accumulate in atherosclerotic lesions and other sites of chronic inflammation. Oxidized PAPC (Ox-PAPC) and its component phospholipid, 1-palmitoyl-2-epoxyisoprostane-sn-glycero-3-phosphorylcholine (PEIPC), activate human aortic endothelial cells (HAEC) in vitro to bind monocytes. Furthermore, these oxidized phospholipids increase the expression and secretion of chemokines known to activate monocytes; elevated levels of these proatherogenic chemokines have also been shown to accumulate within the vessel wall (1Berliner J.A. Kim A.D. N. Engl. J. Med. 2005; 353: 9-11Crossref PubMed Scopus (218) Google Scholar). Thus, we propose that Ox-PAPC plays an important role in regulating atherosclerosis. Interleukin 8 (IL-8), an important mediator of monocyte transmigration and retention in vessel wall, is one such chemokine strongly induced in HAEC treated with Ox-PAPC. IL-8 plays an important role in the regulation of atherosclerosis. Boisvert et al. (2Boisvert W.A. Kim R. Curtiss L.K. Terkeltaub R.A. J. Clin. Investig. 1998; 101: 353-363Crossref PubMed Scopus (440) Google Scholar) demonstrated that knock-out mice of the homologue of IL-8 had reduced levels of atherosclerotic lesions. We recently demonstrated a role for c-Src kinase in the regulation of Ox-PAPC- and PEIPC-induced IL-8 synthesis in HAEC (3Yeh M. Kim N. de Martin R. Onai N. Matsushima K. Vora D.K. Berliner J.A. Reddy S.T. Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1585-1591Crossref PubMed Scopus (101) Google Scholar, 4Yeh M. Kim N.M. Choi J. Hsieh X. Reed E. Mouillesseaux K.P. Cole A.L. Reddy S.T. Berliner J.A. J. Biol. Chem. 2004; 279: 30175-30181Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). In these studies, we also presented evidence that activation of signal transducer and activator of transcription (STAT) 3 might be involved in Ox-PAPC-induced IL-8 transcription. Downstream of c-Src, however, the mechanism of IL-8 transcription by Ox-PAPC remained to be examined. In this study, we have defined the mechanism of c-Src-mediated IL-8 transcription by Ox-PAPC. Previous studies by others had demonstrated interaction between Src kinases and JAK kinases, including their role in regulating several inflammatory processes (5Bhattacharya S. Kim R.M. Johnson L.R. Biochem. J. 2006; 397: 437-447Crossref PubMed Scopus (31) Google Scholar, 6Ingley E. Kim S.P. Growth Factors. 2006; 24: 89-95Crossref PubMed Scopus (40) Google Scholar, 7Proietti C. Kim M. Rosemblit C. Carnevale R. Pecci A. Kornblihtt A.R. Molinolo A.A. Frahm I. Charreau E.H. Schillaci R. Elizalde P.V. Mol. Cell. Biol. 2005; 25: 4826-4840Crossref PubMed Scopus (116) Google Scholar). The JAK family consists of four members in mammals, JAK1–3, and TYK2 (8Verma A. Kim S. Parmar S. Platanias L.C. Cancer Metastasis Rev. 2003; 22: 423-434Crossref PubMed Scopus (117) Google Scholar). Although JAK1, JAK2, and TYK2 are expressed in all cell types (9Rane S.G. Kim E.P. Oncogene. 2000; 19: 5662-5679Crossref PubMed Scopus (380) Google Scholar), including human endothelial cells, the expression of JAK3 is restricted to cells of the myeloid and lymphoid lineages (10Leonard W.J. Kim J.J. Annu. Rev. Immunol. 1998; 16: 293-322Crossref PubMed Scopus (1480) Google Scholar). JAK activation is mediated by phosphorylation of specific tyrosine residues (9Rane S.G. Kim E.P. Oncogene. 2000; 19: 5662-5679Crossref PubMed Scopus (380) Google Scholar); phosphorylation of tyrosine residues 1007/1008 is a marker of JAK2 activation (11Chatti K. Kim W.L. Duhe R.J. Biochemistry. 2004; 43: 4272-4283Crossref PubMed Scopus (36) Google Scholar). JAKs are activated by autophosphorylation via direct association with cell surface receptors (9Rane S.G. Kim E.P. Oncogene. 2000; 19: 5662-5679Crossref PubMed Scopus (380) Google Scholar), such as the interferon (IFN) receptor (12Qing Y. Kim G.R. J. Biol. Chem. 2004; 279: 41679-41685Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar), or through interaction with tyrosine kinases, such as the Src family of kinases (13Lo R.K. Kim H. Wong Y.H. J. Biol. Chem. 2003; 278: 52154-52165Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). The major action of JAK is to promote gene transcription by activating STAT proteins (14Rane S.G. Kim E.P. Oncogene. 2002; 21: 3334-3358Crossref PubMed Scopus (203) Google Scholar). To date, seven mammalian STAT proteins have been identified, referred to as STAT1–4, -5A, -5B, and -6 (15Darnell Jr., J.E. Science. 1997; 277: 1630-1635Crossref PubMed Scopus (3383) Google Scholar). STAT3 activation can be detected as phosphorylation of tyrosine 705 and serine 727 (16Bhattacharjee A. Kim B. Frank D.A. Feldman G.M. Cathcart M.K. J. Immunol. 2006; 177: 3771-3781Crossref PubMed Scopus (24) Google Scholar). Once activated, STAT proteins homo- or heterodimerize and translocate into the nucleus, where they activate gene transcription through binding to specific promoter response elements (17Kisseleva T. Kim S. Braunstein J. Schindler C.W. Gene (Amst.). 2002; 285: 1-24Crossref PubMed Scopus (907) Google Scholar). Most STAT dimers recognize and bind to members of the γ-IFN activation sequence (GAS) (18Decker T. Kim P. Meinke A. J. Interferon Cytokine Res. 1997; 17: 121-134Crossref PubMed Scopus (341) Google Scholar) or the IFN-stimulated response element (19Kessler D.S. Kim D.E. Darnell Jr., J.E. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 8521-8525Crossref PubMed Scopus (170) Google Scholar) family of enhancers to promote gene transcription; to date, homodimerized STAT3 has only been shown to have affinity for and bind to the GAS (20Yang C.H. Kim A. Pfeffer L.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5568-5572Crossref PubMed Scopus (119) Google Scholar, 21Yang C.H. Kim L. Pfeffer S.R. Du Z. Murti A. Valentine W.J. Zheng Y. Pfeffer L.M. J. Immunol. 2007; 178: 986-992Crossref PubMed Scopus (42) Google Scholar). In this study, we have demonstrated that in response to Ox-PAPC treatment, c-Src kinase activates JAK2, which subsequently phosphorylates and activates STAT3. Activated STAT3 then translocates into the nucleus and binds to a GAS element in the IL-8 promoter, which regulates IL-8 transcription. We have also demonstrated a role for endothelial STAT3 in atherosclerosis in mice, as well as the presence of activated STAT3 in the inflammatory regions of human atherosclerotic lesions. These findings suggest that STAT3 activation by oxidized phospholipids may be an important therapeutic target for treatment of atherosclerosis. and for HAEC was for was was PAPC was Oxidized phospholipids as Kim H. E. Berliner J.A. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). against JAK2 and STAT3 STAT3 Src as well as the STAT3 against and against JAK2, and the studies, STAT3 was and STAT3 was and the aortic of and as N.M. Kim Mouillesseaux K.P. Hsieh X. M. Berliner J.A. Res. 2006; PubMed Scopus Google Scholar). HMEC, the for and Kim R.A. S. J. Investig. Full Text PDF PubMed Google Scholar), as M. Kim N.M. Choi J. Hsieh X. Reed E. Mouillesseaux K.P. Cole A.L. Reddy S.T. Berliner J.A. J. Biol. Chem. 2004; 279: 30175-30181Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Treatment with and other activating was in with endothelial cells and and in as Kim A.L. M. S.R. R.M. J. Vora D.K. Berliner J.A. Arterioscler. Thromb. Vasc. Biol. 2003; PubMed Scopus Google Scholar). for the as N.M. Kim Mouillesseaux K.P. Hsieh X. M. Berliner J.A. Res. 2006; PubMed Scopus Google Scholar). Western as N.M. Kim Mouillesseaux K.P. Hsieh X. M. Berliner J.A. Res. 2006; PubMed Scopus Google Scholar). in and on The then for specific binding to for the was and with for of the levels of levels in cell measured with an IL-8 to the the human IL-8 promoter to K. Matsushima of K. Kim S. N. S. M. Matsushima K. J. Biol. Chem. Full Text PDF PubMed Google Scholar). JAK2 which a in kinase was by of S. Kim M. Z. R. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). in the GAS element in the with a site-directed mutagenesis and by the as (3Yeh M. Kim N. de Martin R. Onai N. Matsushima K. Vora D.K. Berliner J.A. Reddy S.T. Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1585-1591Crossref PubMed Scopus (101) Google Scholar) and The GAS found was to Transfection of in with cells in with of of of and of the or well and Transfection as M. Kim N.M. Choi J. Hsieh X. Reed E. Mouillesseaux K.P. Cole A.L. Reddy S.T. Berliner J.A. J. Biol. Chem. 2004; 279: 30175-30181Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). activity, to was Transfection of RNA against and the and of by and It was found that with a reduced of the and IL-8 HAEC in a for 3 with or and of in of cells and in and to an Using for IL-8 and as and and JAK2, and and was and data as N.M. Kim Mouillesseaux K.P. Hsieh X. M. Berliner J.A. Res. 2006; PubMed Scopus Google Scholar). the chromatin immunoprecipitation to the with the of The and that sequence flanking GAS element of in the IL-8 gene promoter and To the GAS element in the IL-8 promoter, we used to transcription binding sequence and sequence downstream of the transcription examined. GAS element was also by the the promoter sequence for the gene of was the and the of the in the IL-8 promoter examined. with in seven on and within in and subsequently and was as Kim 2003; PubMed Scopus Google Scholar). with of and with for in and with a STAT3 the laboratory of A. Kim J. Y. R.A. J. Med. 2003; PubMed Scopus Google Scholar). mice, in which expression was by the promoter the laboratory of J.A. Kim A. T. A. P. 2006; PubMed Scopus Google Scholar). mice a of the and then with mice, which on the The with to and mice 8 of mice the atherogenic and for subsequently for and by for in as Kim C.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of the and quantitative of as Kim C.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar). was also examined staining with of The of in the with was We only cells with an Ox-PAPC and Treatment of HAEC treatment of HAEC with Ox-PAPC and its PEIPC, activated JAK2, phosphorylation of JAK2 was examined Western Ox-PAPC and JAK2 detected an increase in phosphorylation within for to treatment with Ox-PAPC and levels of JAK2 remained all treatment with Ox-PAPC and Using we the activation of JAK2 by the of Ox-PAPC- or PEIPC-induced to that of several their Ox-PAPC treatment of HAEC induced a increase in JAK2 phosphorylation treatment induced a increase We also examined the activation of Ox-PAPC Our findings demonstrated that Ox-PAPC treatment of HAEC the levels of a marker of activation These findings demonstrated that treatment of HAEC with Ox-PAPC and activated JAK2, JAK1, in a yet sustained In a previous M. Kim N.M. Choi J. Hsieh X. Reed E. Mouillesseaux K.P. Cole A.L. Reddy S.T. Berliner J.A. J. Biol. Chem. 2004; 279: 30175-30181Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), we demonstrated activation of c-Src kinase in HAEC Ox-PAPC The interaction between c-Src and JAK2 has been in other (13Lo R.K. Kim H. Wong Y.H. J. Biol. Chem. 2003; 278: 52154-52165Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar, A. Kim M. K. N. T. J. 2005; PubMed Scopus Google Scholar). findings demonstrated that Ox-PAPC-induced JAK2 activation was sustained for to c-Src activation was rapid and we that activation of JAK2 was downstream of c-Src To Ox-PAPC-induced JAK2 activation was mediated c-Src we the of c-Src kinase activity, and its of HAEC with Ox-PAPC-induced JAK2 phosphorylation JAK2 levels remained four a in JAK2 activation with Furthermore, we that the of on JAK2 activation was specific to Ox-PAPC, the activation of JAK2 by a known JAK2 activator of JAK2 Ox-PAPC- and PEIPC-induced IL-8 the that JAK2 plays a role in Ox-PAPC-induced IL-8 we the selective JAK2 JAK2 with an in the and as as have been shown to have on the of Src kinases N. Kim T. H. M. E. Z. M. A. A. A. PubMed Scopus Google Scholar). In studies, we also on phosphorylation of of c-Src in response to of HAEC with a in Ox-PAPC-induced IL-8 protein as measured by of HAEC with also significantly reduced the of IL-8 protein synthesis by the of IL-8 protein synthesis by Ox-PAPC is mediated the transcription we examined the role of JAK2 in Ox-PAPC-induced IL-8 of HAEC with significantly reduced the levels of IL-8 induced by Ox-PAPC and treatment, as measured by In this we also demonstrated that the to Ox-PAPC-induced IL-8 transcription Furthermore, pretreatment of HAEC with the levels of c-Src activation by Ox-PAPC presented as in of Src phosphorylation this cells with for by a treatment with Ox-PAPC for Src To the role of JAK2 in regulating Ox-PAPC-induced IL-8 we examined the of a JAK2 on IL-8 promoter In HMEC, of a in Ox-PAPC-induced IL-8 promoter activation by as with These findings demonstrated that JAK2 activation regulates the of IL-8 transcription by Ox-PAPC. JAK2 IL-8 through examined the mechanism by which JAK2 activation Ox-PAPC-induced IL-8 transcription. Previously, we had a role for STAT3 in IL-8 transcription by Ox-PAPC. we examined the role of JAK2 on the activation of STAT3 by Ox-PAPC. these studies, to JAK2 was Treatment of HAEC with to JAK2 JAK2 levels by as with with Furthermore, JAK2 inhibited Ox-PAPC-induced STAT3 as measured by phosphorylation has on STAT3 levels was in several we examined the role of STAT3 in Ox-PAPC-induced IL-8 transcription against STAT3. STAT3 is of and the used in studies the Our findings demonstrated a in levels with the STAT3 siRNA, as with with Furthermore, STAT3 significantly reduced the levels of IL-8 induced by Ox-PAPC in HAEC, as with with These findings demonstrated that JAK2 activation IL-8 transcription in HAEC through STAT3 of the GAS in the IL-8 and in IL-8 by the mechanism by which STAT3 IL-8 transcription by Ox-PAPC, we examined the human IL-8 promoter for a sequence to the known STAT3 response sequence was in the IL-8 promoter of which was to the consensus GAS in all To the of the consensus GAS element in Ox-PAPC to STAT3 bind to the IL-8 Our findings demonstrated that Ox-PAPC treatment induced the binding of STAT3 to the sequence flanking the consensus GAS in the IL-8 Furthermore, the of STAT3 was demonstrated to be the activated, of STAT3 for the binding of STAT3 to the IL-8 promoter was also demonstrated which bind to this promoter sequence Treatment with was used as and the levels all We examined the of this GAS element in IL-8 promoter activation by Ox-PAPC by a of the in this sequence with the or the and IL-8 promoter activation Ox-PAPC treatment was Our demonstrated that the GAS significantly reduced activation of the IL-8 promoter by Ox-PAPC which IL-8 transcription through activation of the and response elements S. Kim N. K. N. Y. H. S. Matsushima K. J. Biol. Chem. Full Text PDF PubMed Google Scholar), was used as a and demonstrated activation of These data demonstrated a direct role for STAT3 in the regulation of IL-8 transcription and the GAS element as an important response element IL-8 promoter activation by Ox-PAPC. In for the of STAT3 in in STAT3 activation plays a role in atherosclerosis in we examined of human atherosclerotic lesions for activated STAT3 We examined and inflammatory of the for binding of the activated In inflammatory of atherosclerotic was staining for in the of endothelial cells and also in the of inflammatory cells. of inhibited endothelial cell staining was staining of the inflammatory cells In in of the or inflammatory cells, STAT3 staining was These findings that endothelial STAT3 activation might an important role in the of inflammatory cells into the human atherosclerotic and that oxidized phospholipids might to this STAT3 In for the of STAT3 in in examined the role of endothelial STAT3 in atherosclerosis in STAT3 knock-out mice by mice a with mice this in which the promoter is an endothelial cell that is expressed and in and endothelial cells Kim L. R. H. U. E. PubMed Google Scholar). Using the et al. J.A. Kim A. T. A. P. 2006; PubMed Scopus Google Scholar) demonstrated that the mice expressed the to a in a small of STAT3 knock-out and mice and on the atherogenic for in or levels the mice had significantly lesions the mice The lesions in these mice all fatty streak lesions as shown in was staining with and was also reduced in the mice These findings the role for STAT3 as an important gene regulating atherosclerosis in vivo. an important role for the pathway in atherosclerosis. Our in vitro studies an important response by this the of IL-8 transcription by oxidized phospholipids that accumulate in atherosclerotic lesions. We demonstrated activation of c-Src within of Ox-PAPC treatment M. Kim N.M. Choi J. Hsieh X. Reed E. Mouillesseaux K.P. Cole A.L. Reddy S.T. Berliner J.A. J. Biol. Chem. 2004; 279: 30175-30181Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). We demonstrate that treatment of HAEC with Ox-PAPC and activates JAK2 and that this activation is sustained for to and Our findings have also demonstrated that activation of JAK2 by Ox-PAPC is dependent on c-Src kinase of JAK2 to Ox-PAPC-induced IL-8 and protein synthesis We also demonstrated that JAK2 STAT3 activation by Ox-PAPC and that STAT3 activation plays a direct role in regulating IL-8 transcription by Ox-PAPC We on STAT3 in these studies we found that Ox-PAPC treatment of HAEC activated STAT3 or (3Yeh M. Kim N. de Martin R. Onai N. Matsushima K. Vora D.K. Berliner J.A. Reddy S.T. Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1585-1591Crossref PubMed Scopus (101) Google Scholar). was examined by the phosphorylation and of and has also an element in the IL-8 promoter, of which is to the consensus GAS Using we demonstrated the binding of activated STAT3 to a sequence flanking the GAS element in the IL-8 promoter Previous studies have demonstrated specific binding of STAT3 to the GAS element (20Yang C.H. Kim A. Pfeffer L.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5568-5572Crossref PubMed Scopus (119) Google Scholar). Furthermore, a in this sequence significantly reduced the activation of the by Ox-PAPC Our findings a in which Ox-PAPC a rapid and increase in c-Src kinase activity, which to the activation of Activated JAK2 subsequently the activation of which translocates into the nucleus, and binds to the GAS element in the IL-8 promoter, IL-8 transcription. Our data previous a role for GAS activation in the regulation of chemokine transcription. Wong et al. P. Kim C.W. Mol. Cell. Biol. PubMed Scopus Google Scholar) and demonstrated a role for GAS in expression of induced by a of the found in role for GAS has also been demonstrated in the induced by other inflammatory including H. Kim J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and J. Kim C. J. T. Schindler C. Mol. Cell. Biol. PubMed Scopus Google Scholar). a previous demonstrated that activated STAT3 and to increase IL-8 expression in cells Kim S.T. 2006; PubMed Scopus Google Scholar). we demonstrated that Ox-PAPC treatment activate yet IL-8 expression in that STAT3 is to IL-8 expression in response to Ox-PAPC or that a is Previously, we that Ox-PAPC of IL-8 transcription was elevated for (3Yeh M. Kim N. de Martin R. Onai N. Matsushima K. Vora D.K. Berliner J.A. Reddy S.T. Arterioscler. Thromb. Vasc. Biol. 2001; 21: 1585-1591Crossref PubMed Scopus (101) Google Scholar). We propose that the pathway regulates the of IL-8 activation of this pathway to levels within Ox-PAPC In we have a involving the activation of endothelial and which is activated of Ox-PAPC treatment and sustained for we propose that the endothelial protein pathway regulates the sustained of IL-8 transcription by Ox-PAPC N.M. Kim Mouillesseaux K.P. Hsieh X. M. Berliner J.A. Res. 2006; PubMed Scopus Google Scholar). has also examined the role of STAT3 activation in atherosclerosis in vivo. We have demonstrated significantly STAT3 activation in the of the inflammatory of human atherosclerotic lesions Activated STAT3 staining was also in in the human a role in this cell as well as in endothelial cells. Furthermore, the we have STAT3 knock-out mice, in which STAT3 was in the and demonstrated reduced fatty streak formation in these mice, as with their Although we the in atherosclerosis in these mice to the of STAT3 in the we the of STAT3 in cells on was expressed in a of cells J.A. Kim A. T. A. P. 2006; PubMed Scopus Google Scholar). Our studies are the to a role for STAT3 in atherosclerosis. activation of the pathway has been in other In a study, et al. C. Kim Biol. Med. 2001; PubMed Scopus Google Scholar) demonstrated activation of JAK2 in in response to oxidized et al. R. Kim H. Y. S. Y. Y. K. A. T. Gene 2003; PubMed Scopus Google Scholar) demonstrated that STAT3 activation in cells formation in mice, and transcription in (16Bhattacharjee A. Kim B. Frank D.A. Feldman G.M. Cathcart M.K. J. Immunol. 2006; 177: 3771-3781Crossref PubMed Scopus (24) Google Scholar). Taken together, these studies suggest that STAT3 activation plays an important role in vessel wall Ox-PAPC and its component phospholipids accumulate only in atherosclerotic also in other sites of chronic inflammation. STAT3 activation has been demonstrated to a role in other chronic inflammatory including T. Kim T. T. T. M. K. S. K. Y. K. K. A. J. Clin. Investig. 2001; PubMed Scopus Google Scholar), K. Kim T. Cytokine Growth Rev. 2002; PubMed Scopus Google Scholar), and R. Kim H. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). this that activation of STAT3 by oxidized phospholipids may be an important target for atherosclerosis as well as other chronic inflammatory We and of for their important to this study, the mice, and on their We also for
Gharavi et al. (Wed,) studied this question.