ERK5 Activation Inhibits Inflammatory Responses via Peroxisome Proliferator-activated Receptor δ (PPARδ) Stimulation

Peroxisome proliferator-activated receptors (PPAR) decrease the production of cytokine and inducible nitric-oxide synthase (iNOS) expression, which are associated with aging-related inflammation and insulin resistance. Recently, the involvement of the induction of heme oxygenase-1 (HO-1) in regulating inflammation has been suggested, but the exact mechanisms for reducing inflammation by HO-1 remains unclear. We found that overexpression of HO-1 and Ru(CO)3Cl22, a carbon monoxide (CO)-releasing compound, increased not only ERK5 kinase activity, but also its transcriptional activity measured by luciferase assay with the transfection of the Gal4-ERK5 reporter gene. This transcriptional activity is required for coactivation of PPARδ by ERK5 in C2C12 cells. Ru(CO)3Cl22 activated PPARδ transcriptional activity via the MEK5/ERK5 signaling pathway. The inhibition of NF-κB activity by ERK5 activation was reversed by a dominant negative form of PPARδ suggesting that ERK5/PPARδ activation is required for the anti-inflammatory effects of CO and HO-1. Based on these data, we propose a new mechanism by which CO and HO-1 mediate anti-inflammatory effects via activating ERK5/PPARδ, and ERK5 mediates CO and HO-1-induced PPARδ activation via its interaction with PPARδ. Peroxisome proliferator-activated receptors (PPAR) decrease the production of cytokine and inducible nitric-oxide synthase (iNOS) expression, which are associated with aging-related inflammation and insulin resistance. Recently, the involvement of the induction of heme oxygenase-1 (HO-1) in regulating inflammation has been suggested, but the exact mechanisms for reducing inflammation by HO-1 remains unclear. We found that overexpression of HO-1 and Ru(CO)3Cl22, a carbon monoxide (CO)-releasing compound, increased not only ERK5 kinase activity, but also its transcriptional activity measured by luciferase assay with the transfection of the Gal4-ERK5 reporter gene. This transcriptional activity is required for coactivation of PPARδ by ERK5 in C2C12 cells. Ru(CO)3Cl22 activated PPARδ transcriptional activity via the MEK5/ERK5 signaling pathway. The inhibition of NF-κB activity by ERK5 activation was reversed by a dominant negative form of PPARδ suggesting that ERK5/PPARδ activation is required for the anti-inflammatory effects of CO and HO-1. Based on these data, we propose a new mechanism by which CO and HO-1 mediate anti-inflammatory effects via activating ERK5/PPARδ, and ERK5 mediates CO and HO-1-induced PPARδ activation via its interaction with PPARδ. Muscle wasting is a major feature of the cachexia associated with diverse pathologies such as cancer, sepsis, diabetes, and aging (1Tisdale M.J. J. Natl. Cancer Inst. 1997; 89: 1763-1773Crossref PubMed Scopus (418) Google Scholar). Several cytokines have been implicated in the pathogenesis of muscle wasting, most notably TNF-α, 2The abbreviations used are: TNF-α, tumor necrosis factor-α; PPAR, peroxisome proliferator-activated receptor; HO-1, heme oxygenase-1; CO, carbon monoxide; ERK5, extracellular signal-regulated kinase 5; MEK5, MAPK/ERK kinase 5; iNOS, inducible nitric-oxide synthase; NF-κB, nuclear factor of κ light chain gene enhancer in B-cells; CA, constitutively active; DN, dominant negative; LacZ, β galactosidase; Ad, adenovirus vector; MAP kinase, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; GST, glutathione S-transferase; siRNA, small interfering RNA; aa, amino acid; tk, thymidine kinase; PPRE, PPAR response element. 2The abbreviations used are: TNF-α, tumor necrosis factor-α; PPAR, peroxisome proliferator-activated receptor; HO-1, heme oxygenase-1; CO, carbon monoxide; ERK5, extracellular signal-regulated kinase 5; MEK5, MAPK/ERK kinase 5; iNOS, inducible nitric-oxide synthase; NF-κB, nuclear factor of κ light chain gene enhancer in B-cells; CA, constitutively active; DN, dominant negative; LacZ, β galactosidase; Ad, adenovirus vector; MAP kinase, mitogen-activated protein kinase; JNK, c-Jun NH2-terminal kinase; GST, glutathione S-transferase; siRNA, small interfering RNA; aa, amino acid; tk, thymidine kinase; PPRE, PPAR response element. a pro-inflammatory cytokine that was originally called “cachectin” (1Tisdale M.J. J. Natl. Cancer Inst. 1997; 89: 1763-1773Crossref PubMed Scopus (418) Google Scholar). In addition, aging-related chronic low grade inflammation by TNF-α plays an important role in insulin resistance (2Lavrovsky Y. Chatterjee B. Clark R.A. Roy A.K. Exp. Gerontol. 2000; 35: 521-532Crossref PubMed Scopus (254) Google Scholar). It has been proposed that chronic inflammation by TNF-α-mediated NF-κB activation and subsequent inducible nitric-oxide synthase (iNOS) induction relates to muscle wasting and insulin resistance as we will explain below. Cai et al. (3Cai D. Frantz J.D. Tawa Jr., N.E. Melendez P.A. Oh B.C. Lidov H.G. Hasselgren P.O. Frontera W.R. Lee J. Glass D.J. Shoelson S.E. Cell. 2004; 119: 285-298Abstract Full Text Full Text PDF PubMed Scopus (1056) Google Scholar) have shown that activation of NF-κB, through muscle-specific transgenic expression of activated IκB kinase β (MIKK), causes profound muscle wasting that resembles clinical cachexia. In contrast, no overt phenotype was seen upon muscle-specific inhibition of NF-κB through expression of IκB suppressor (MISR), and denervation and tumor-induced muscle loss were substantially reduced and survival rates improved by NF-κB inhibition in MISR mice, which is consistent with a critical role for NF-κBin the pathology of muscle wasting, especially in diabetes and during the process of aging (3Cai D. Frantz J.D. Tawa Jr., N.E. Melendez P.A. Oh B.C. Lidov H.G. Hasselgren P.O. Frontera W.R. Lee J. Glass D.J. Shoelson S.E. Cell. 2004; 119: 285-298Abstract Full Text Full Text PDF PubMed Scopus (1056) Google Scholar). Recent studies suggest the involvement of iNOS in the pathogenesis of insulin resistance (4Perreault M. Marette A. Nat. Med. 2001; 7: 1138-1143Crossref PubMed Scopus (416) Google Scholar, 5Sugita H. Fujimoto M. Yasukawa T. Shimizu N. Sugita M. Yasuhara S. Martyn J.A. Kaneki M. J. Biol. 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Med. 2001; 7: 1138-1143Crossref PubMed Scopus (416) Google Scholar) showed that the knockout of iNOS specifically from skeletal muscle protects against high fat diet-induced insulin resistance in mice (4Perreault M. Marette A. Nat. Med. 2001; 7: 1138-1143Crossref PubMed Scopus (416) Google Scholar). These data suggest the pathological role of a proinflammatory cytokine, TNF-α, on muscle wasting and insulin resistance via activating NF-κB and induction of iNOS in skeletal muscle. Heme oxygenases (HO) are the rate-limiting enzymes in the of heme to carbon monoxide and have been The dominant in muscle is HO-1, which is by and T. J. 2002; PubMed Scopus Google Scholar). has been that HO-1 is in patients with type 2 diabetes with J.A. Diabetes. PubMed Scopus Google Scholar). In addition, et al. H. B. J. 2000; PubMed Google Scholar) have shown that is a increase of HO-1 expression associated with fatty expression in response to HO-1 against proinflammatory cytokines K. K. Y. S. H. T. H. T. 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The luciferase was used for of cells were with reporter and with as in the and of C2C12 cells were in and in with for to cells skeletal muscle cells. the cells were in a with the and and cells were and with was The of a in is of the luciferase gene. and and and were with PPARδ and ERK5, as also the luciferase the expression and transfection were with the luciferase were transfection as and the luciferase activity was with the luciferase a In the of the for the ERK5 transcriptional activity, cells were with and and to Ru(CO)3Cl22, for the were in and was In of PPARδ by protein was in and as by the ERK5 activity was measured as M. S. M. B. B.C. C. J. Cell. Biol. 2004; PubMed Scopus Google Scholar). by activated ERK5, we an ERK5 in kinase assay with as the and cells were with and in of as S. J. 2002; PubMed Scopus Google Scholar). was as with M. S. M. B. B.C. C. J. Cell. Biol. 2004; PubMed Scopus Google Scholar) was as M. S. M. B. B.C. C. J. Cell. Biol. 2004; PubMed Scopus Google Scholar). In the were for with the (1Tisdale M.J. J. Natl. Cancer Inst. 1997; 89: 1763-1773Crossref PubMed Scopus (418) Google Scholar), iNOS HO-1, and and by with were was a from Ru(CO)3Cl22 from of the were from The and was from was used as a negative The C2C12 cells were with the transfection the by the The cells were and protein expression was measured with against ERK5 are as was with the were with of as by for are by a and by HO-1 and Ru(CO)3Cl22 to TNF-α in Muscle the of HO-1 and a CO compound, Ru(CO)3Cl22, on proinflammatory in skeletal muscle we these effects on TNF-α-mediated NF-κB shown in HO-1 induction and Ru(CO)3Cl22 TNF-α-mediated NF-κB iNOS expression in skeletal muscle has a role in and subsequent insulin resistance especially in the (4Perreault M. Marette A. Nat. Med. 2001; 7: 1138-1143Crossref PubMed Scopus (416) Google Scholar, 5Sugita H. Fujimoto M. Yasukawa T. Shimizu N. Sugita M. Yasuhara S. Martyn J.A. Kaneki M. J. Biol. Chem. 2005; 280: 14203-14211Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar), we induction of HO-1 and Ru(CO)3Cl22 TNF-α-mediated iNOS expression. We found that the induction of iNOS in response to TNF-α was by HO-1 induction and CO These data suggest an anti-inflammatory role for HO-1 induction as as subsequent CO in skeletal muscle. HO-1 and ERK5 and the of HO-1 and the subsequent HO-1 CO on ERK5 we adenovirus HO-1 to C2C12 cells and that ERK5 kinase activation was increased we the C2C12 skeletal muscle cells with We found that Ru(CO)3Cl22 increased ERK5 kinase activation from to Ru(CO)3Cl22 and ERK5 which kinase activity, was increased by Ru(CO)3Cl22 and we the Gal4-ERK5 to ERK5 transcriptional activity M. S. M. B. B.C. C. J. Cell. Biol. 2004; PubMed Scopus Google Scholar). We and ERK5 transcriptional activity by and shown in and we found that of and Ru(CO)3Cl22 increased ERK5 transcriptional We also the of Ru(CO)3Cl22 with ERK5 such as insulin factor Ru(CO)3Cl22 ERK5 transcriptional activity as the the role of Ru(CO)3Cl22 and ERK5 transcriptional of ERK5 PPARδ and in to we that transcriptional activity was increased by ERK5 in cells M. S. M. B. B.C. C. J. Cell. Biol. 2004; PubMed Scopus Google Scholar). in we ERK5 increase PPARδ activity in skeletal muscle of the expression of PPARδ in skeletal muscle S. J. D. A. J. M. P.A. J. PubMed Scopus Google Scholar). We PPARδ and the constitutively form of in C2C12 cells and transcriptional activity, as by a luciferase reporter gene by of a PPAR response to a thymidine kinase shown in increased PPARδ transcriptional activity, and also PPARδ PPARδ transcriptional PPARδ expression were not the on not PPARδ activation has been to Y. N. T. M. D. A. J. 2002; PubMed Scopus Google Scholar), we the role of PPARδ activation on TNF-α-mediated We found that PPARδ TNF-α-mediated NF-κB activation and subsequent iNOS induction we found that activation of ERK5 increased PPARδ transcriptional activity, we activation of ERK5 TNF-α-mediated We adenovirus and NF-κB reporter and of transfection C2C12 cells were with TNF-α for and NF-κB activity was by luciferase shown in activation of ERK5 TNF-α-mediated NF-κB the role of ERK5 activation as an inflammation we also the role of and on TNF-α-mediated NF-κB activity the constitutively of and We that transfection of these increase and c-Jun transcriptional activity, not shown in and we found that and have no on TNF-α-mediated NF-κB activation in C2C12 suggesting the anti-inflammatory of activation on TNF-α-mediated NF-κB we found that of TNF-α-mediated iNOS induction and these data suggest that PPARδ and ERK5 the response by ERK5 and PPARδ for the of CO on TNF-α-mediated NF-κB we found that HO-1 induction and Ru(CO)3Cl22 increased ERK5 activation and activation of ERK5 increase PPARδ transcriptional activity, we Ru(CO)3Cl22 increase PPARδ transcriptional activity via ERK5 We a dominant negative form of ERK5 with the NF-κB reporter and of we the cells with Ru(CO)3Cl22 for and PPARδ transcriptional shown in we found that Ru(CO)3Cl22 increased PPARδ activity and the of PPARδ we not of on the PPARδ PPARδ activity not We inhibition of PPARδ activity by transfection of suggesting the critical role of ERK5 activation on but not PPARδ PPARδ of the by the low transfection of the reporter gene in C2C12 reporter gene assay showed the of PPARδ activation by Ru(CO)3Cl22 is to that by the PPARδ and PPARδ has a on TNF-α-mediated as we and A. N. D. PubMed Scopus Google Scholar, Y. N. T. M. D. A. J. 2002; PubMed Scopus Google Scholar, J. J.A. 2002; PubMed Scopus Google Scholar). we that PPARδ activation by Ru(CO)3Cl22 has a pathological in skeletal muscle. the role of ERK5 activation on PPARδ transcriptional we ERK5 to its expression. In C2C12 cells the transfection of ERK5 but not ERK5 expression shown in we found that PPARδ activity was impaired by of ERK5 expression in C2C12 cells. These data also the critical role of ERK5 in PPARδ transcriptional the involvement of and activation on PPARδ we used the shown in and the dominant negative form of ERK5 PPARδ and showed no on PPARδ also suggesting the role of MEK5/ERK5 on PPARδ the role for ERK5/PPARδ activation by Ru(CO)3Cl22, we the role of ERK5 activation in the of Ru(CO)3Cl22 on TNF-α-mediated NF-κB PPARδ we the of Ru(CO)3Cl22 on TNF-α-mediated NF-κB shown in the of Ru(CO)3Cl22 to decrease the TNF-α-mediated NF-κB These data suggest that the of Ru(CO)3Cl22 on NF-κB is to the activation of to the involvement of PPARδ activation of inhibition of NF-κB we a dominant negative form of PPARδ shown in and PPARδ TNF-α-mediated NF-κB of the of ERK5 activation on NF-κB activation and suggesting that the of ERK5 activation is to its activation of PPARδ. ERK5 PPARδ in but with activation of ERK5 PPARδ activity, we ERK5 PPARδ in We and ERK5 in cells to ERK5 ERK5 was with an and in kinase assay was with and PPARδ as shown in transfection of activated ERK5 kinase, as shown by ERK5 ERK5 not PPARδ we that ERK5 transcriptional activity via the ERK5 and M. S. M. B. B.C. C. J. Cell. Biol. 2004; PubMed Scopus Google Scholar). to the interaction ERK5 and we interaction PPARδ is a nuclear and ERK5 to activated for its nuclear Y. J. Lee J.D. 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Biol. 2004; PubMed Scopus Google Scholar). we the of PPARδ on shown in we found that the of of PPARδ with ERK5, which is from suggesting that ERK5 with the of PPARδ. The of ERK5 to PPARδ for PPARδ we that the ERK5 high transcriptional activity transfection M. S. M. B. B.C. C. J. Cell. Biol. 2004; PubMed Scopus Google Scholar). to the role of ERK5/PPARδ on PPARδ we the ERK5 shown in the ERK5 which the PPARδ and increased PPARδ the the of ERK5 not PPARδ activity, suggesting a critical role for the of ERK5 as a of ERK5 with PPARδ. In the we HO-1 and CO TNF-α-mediated in skeletal which are to for insulin resistance in the We found that CO and induction of HO-1 TNF-α-mediated the mechanism of anti-inflammatory effects of CO and HO-1 we MAP kinase activation by Ru(CO)3Cl22 and HO-1 and found that ERK5 activated by Ru(CO)3Cl22 and HO-1. we that the of by ERK5 kinase and PPARδ is the major in the skeletal we ERK5 PPARδ of ERK5 increased PPARδ transcriptional activity, and PPARδ transcriptional activity was by In addition, the inhibition of ERK5 activation was reversed by the the that ERK5/PPARδ activation is required for an anti-inflammatory of CO and HO-1. Finally, we found that ERK5/PPARδ is critical for PPARδ Based on these data, we propose a new mechanism by which CO and HO-1 mediates the anti-inflammatory via activating The role of HO-1 has been in of cells including skeletal muscle S. J. 2002; PubMed Scopus Google Scholar), J.A. L. Y. Lee A. K. S. R. J. PubMed Scopus Google Scholar), F. D. J. S. D.J. M. 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Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar), ERK5 with PPARδ which is from suggesting that the ERK5 have an on ERK5/PPARδ These data also suggest the mechanism of ERK5 on PPARδ which is from studies are required to the role of the PPARδ with Recently, J. H. Biol. 2004; PubMed Scopus Google Scholar, S. J. D. A. J. M. P.A. J. PubMed Scopus Google Scholar) the phenotype of skeletal muscle-specific PPARδ showed increased fatty expression in skeletal and et al. Lee S. J. H. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) found that high fat diet-induced insulin resistance was improved in PPARδ transgenic et al. Lee S. J. H. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) have that mice with a high fat showed reduced and were to These data suggest a critical role for PPARδ in regulating insulin by expression and activity, in skeletal muscle. It is also that the of PPARδ insulin aging-related chronic low grade inflammation plays an important role in insulin resistance (2Lavrovsky Y. Chatterjee B. Clark R.A. Roy A.K. Exp. Gerontol. 2000; 35: 521-532Crossref PubMed Scopus (254) Google Scholar), and is that chronic iNOS induction causes muscle insulin resistance (4Perreault M. Marette A. Nat. Med. 2001; 7: 1138-1143Crossref PubMed Scopus (416) Google Scholar). is required to the role of HO-1 and ERK5 in the aging We are to and for PPARδ and the compound, for and F. for and for