Skip to main content

Advertisement

SpringerLink
Log in

Activation of PPAR-γ by Carbon Monoxide from CORM-2 Leads to the Inhibition of iNOS but not COX-2 Expression in LPS-Stimulated Macrophages

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

The effect of CO on the expression of iNOS and COX-2 was investigated by using a CO-releasing molecule (CORM)-2 in LPS-activated RAW 264.7 cells in vitro. Interestingly, CORM-2 significantly inhibited iNOS (NO) but not COX-2 (PGE2) expression. PPAR-γ activators such as troglitazone, GW1929, and 15-deoxy-Δ12, 14- prostaglandin J2 showed preferential inhibitory effect on iNOS over COX-2 expression in LPS-activated macrophages. The same effect was shown in lung tissues (iNOS, COX-2) and serum (NO, PGE2) when administered of CORM-2 in LPS-induced septic mice, indicating that CO derived from CORM-2 differentially regulates iNOS and COX-2 through PPAR-γ activation under inflammation state.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Xie, Q. W., Y. Kashiwabara, and C. Nathan. 1994. Role of transcription factor NF-κB/Rel in induction of nitric oxide synthase. J. Biol. Chem. 269:4705–4708.

    CAS  PubMed  Google Scholar 

  2. Nakao, S., Y. Ogata, E. Shimizu-Sasaki, M. Yamazaki, S. Furuyama, and H. Sugiya. 2000. Activation of NF-kappaB is necessary for IL-1beta-induced cyclooxygenase-2 (COX-2) expression in human gingival fibroblasts. Mol. Cell Biochem. 209:113–118.

    Article  CAS  PubMed  Google Scholar 

  3. Wang, X. M., H. P. Kim, K. Nakahira, S. W. Ryter, and A. M. Choi. 2009. The heme oxygenase-1/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1. J. Immunol. 182:3809–3818.

    Article  CAS  PubMed  Google Scholar 

  4. Alcaraz, M. J., M. I. Guillen, M. L. Ferrandiz, J. Megias, and R. Motterlini. 2008. Carbon monoxide-releasing molecules: a pharmacological expedient to counteract inflammation. Curr. Pharm. Des. 14:465–472.

    Article  CAS  PubMed  Google Scholar 

  5. Sun, J. J., H. J. Kim, H. G. Seo, J. H. Lee, H. S. Yun-Choi, and K. C. Chang. 2008. YS 49, 1-(alpha-naphtylmethyl)-6, 7-dihydroxy-1, 2, 3, 4-tetrahydroisoquinoline, regulates angiotensin II-stimulated ROS production, JNK phosphorylation and vascular smooth muscle cell proliferation via the induction of heme oxygenase-1. Life Sci. 82:600–607.

    Article  CAS  PubMed  Google Scholar 

  6. Chung, S. W., X. Liu, A. A. Macias, R. M. Baron, and M. A. Perrella. 2008. Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice. J. Clin. Invest. 118:239–247.

    Article  CAS  PubMed  Google Scholar 

  7. Ryter, S. W., J. Alam, and A. M. Choi. 2006. Heme oxygenase/carbon monoxide: from basic science to therapeutic application. Physiol. Rev. 86:583–650.

    Article  CAS  PubMed  Google Scholar 

  8. Vane, J. R., J. A. Mitchell, I. Appelton, A. Tomlinson, D. Bishop-Bailey, J. Croxtall, and D. A. Willoughby. 1994. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc. Natl. Acad. Sci. U. S. A. 91:2046–2050.

    Article  CAS  PubMed  Google Scholar 

  9. Welch, J. S., M. Ricote, T. E. Akiyama, F. J. Gonzales, and C. K. Glass. 2003. PPARgamma and PPARdelta negatively regulate specific subsets of lipoposaccharide and IFN-gamma target genes in macrophage. Proc. Natl. Acad. Sci. U. S. A. 100:6712–6717.

    Article  CAS  PubMed  Google Scholar 

  10. Kang, Y. J., E. B. Koo, Y. S. Lee, H. S. Yun-Choi, and K. C. Chang. 1999. Prevention of the expression of inducible nitric oxide synthase by novel positive inotropic agent, YS 49, in rat vascular smooth muscle and RAW 264.7 macrophages. Br. J. Pharmacol. 128:357–364.

    Article  CAS  PubMed  Google Scholar 

  11. Otterbein, L. E., F. H. Bach, J. Alam, M. Soares, H. Tao Lu, M. Wysk, R. J. Davis, R. A. Flavell, and A. M. Choi. 2000. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat. Med. 6:422–428.

    Article  CAS  PubMed  Google Scholar 

  12. Motterlini, R., J. E. Clark, R. Foresti, P. Sarathchandra, B. E. Mann, and C. J. Green. 2002. Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities. Circ. Res. 90:E17–E24.

    Article  CAS  PubMed  Google Scholar 

  13. Nobre, L. S., F. Al-Shahrouh, J. Dopazo, and L. M. Saraiva. 2009. Exploring the antimicrobial action of a carbon monoxide-releasing compound through whole-genome transcription profiling of Escherichia coli. Microbiology 155:813–824.

    Article  CAS  PubMed  Google Scholar 

  14. Davidge, K. S., G. Sanguinetti, C. H. Yee, A. G. Cox, C. W. McLeod, C. E. Monk, B. E. Mann, R. Motterlini, and R. K. Poole. 2009. Carbon monoxide-releasing antibacterial molecules target respiration and global transcriptional regulators. J. Biol. Chem. 284:4516–4524.

    Article  CAS  PubMed  Google Scholar 

  15. Guillen, M. I., J. Megias, V. Clerigues, F. Gomar, and M. J. Alcaraz. 2008. The CO-releasing molecule CORM-2 is a novel regulator of the inflammatory process in osteoarthritic chondrocytes. Rheumatology (Oxford) 47:1323–1328.

    Article  CAS  Google Scholar 

  16. De Backer, O., E. Elinck, P. Sips, E. Buys, P. Brouckaert, and R. A. Lefebvre. 2008. Role of the soluble guanylyl cyclase alpha1/alpha2 subunits in the relaxant effect of CO and CORM-2 in murine gastric fundus. Naunyn Schmiedebergs. Arch. Pharmacol. 378:493–502.

    Article  Google Scholar 

  17. Masini, E., A. Vannacci, P. Failli, R. Mastroianni, L. Giannini, M. C. Vinci, C. Uliva, R. Motterlini, and P. F. Mannaioni. 2008. A carbon monoxide-releasing molecule (CORM-3) abrogates polymorphonuclear granulocyte-induced activation of endothelial cells and mast cells. FASEB J. 22:3380–3388.

    Article  CAS  PubMed  Google Scholar 

  18. Davies, A. L., A. L. Kramer, and K. C. Hayes. 2008. Carbon monoxide-releasing molecule tricarbonyldichlororuthenium (II) dimmer induces concentration-dependent alterations in the electrophysiological properties of axons in mammalian spinal cord. Neuroscience 151:1104–1111.

    Article  CAS  PubMed  Google Scholar 

  19. Sawle, P., R. Foresti, B. E. Mann, T. R. Johnson, C. J. Green, and R. Motterlini. 2005. Carbon monoxide-releasing molecules (CO-RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW2647 murine macrophages. Br. J. Pharmacol. 145:800–810.

    Article  CAS  PubMed  Google Scholar 

  20. Sarady, J. K., B. S. Zuckerbraun, M. Bilban, O. Wagner, A. Usheva, F. Liu, E. Ifedigbo, R. Zamora, A. M. Choi, and L. E. Otterbein. 2004. Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver. FASEB J. 18:854–856.

    PubMed  Google Scholar 

  21. Bilban, M., F. H. Bach, S. L. Otterbein, E. Ifedigbo, J. C. d’Avila, H. Esterbauer, B. Y. Chin, A. Usheva, S. C. Robson, O. Wagner, and L. E. Otterbein. 2006. Carbon monoxide orchestrates a protective response through PPARγ. Immunity 24:601–610.

    Article  CAS  PubMed  Google Scholar 

  22. Hoetzel, A., T. Dolinay, S. Vallbracht, Y. Zhang, H. P. Kim, E. Ifedigbo, S. Alber, A. M. Kaynar, R. Schmidt, S. W. Ryter, and A. M. Choi. 2008. Carbon monoxide protects against ventilator-induced lung injury via PPAR-gamma and inhibition of Egr-1. Am. J. Respir. Crit. Care Med. 177:1223–1232.

    Article  CAS  PubMed  Google Scholar 

  23. Suh, G. Y., Y. Jin, A. K. Yi, X. M. Wang, and A. M. Choi. 2006. CCAAT/enhancer-binding protein mediates carbon monoxide-induced suppression of cyclooxygenase-2. Am. J. Respir. Mol. Cell. Biol. 35:220–226.

    Article  CAS  Google Scholar 

  24. Cheng, C., Y. Qin, X. Shao, H. Wang, Y. Gao, M. Cheng, and A. Shen. 2007. Induction of TNF-alpha by LPS in Schwann cell is regulated by MAPK activation signals. Cell Mol. Neurobiol. 27:909–921.

    Article  CAS  PubMed  Google Scholar 

  25. Wang, H., C. Cheng, Y. Qin, S. Niu, S. Gao, X. Li, T. Tao, and A. Shen. 2009. Role of mitogen-activated protein kinase cascades in inducible nitric oxide synthase expression by lipopolysaccharide in a rat schwann cell line. Neurochem. Res. 34:430–437.

    Article  CAS  PubMed  Google Scholar 

  26. Nakao, A., D. J. Kaczorowski, B. S. Zuckerbraun, J. Lei, G. Faleo, K. Deguchi, K. R. McCurry, T. R. Billiar, and S. Kanno. 2008. Galantamine and carbon monoxide protect brain microvascular endothelial cells by heme oxygenase-1 induction. Biochem. Biophys. Res. Commun. 367:674–679.

    Article  CAS  PubMed  Google Scholar 

  27. Kim, K. M., H. O. Pae, M. Zhung, H. Y. Ha, Y. A. Ha, K. Y. Chai, Y. K. Cheong, J. M. Kim, and H. T. Chung. 2008. Involvement of anti-inflammatory heme oxygenase-1 in the inhibitory effect of curcumin on the expression of pro-inflammatory inducible nitric oxide synthase in RAW264.7 macrophages. Biomed. Pharmacother. 62:630–636.

    Article  CAS  PubMed  Google Scholar 

  28. Tsoyi, K., H. J. Kim, J. S. Shin, D. H. Kim, H. J. Cho, S. S. Lee, S. K. Ahn, H. S. Yun-Choi, J. H. Lee, H. G. Seo, and K. C. Chang. 2008. HO-1 and JAK-2/STAT-1 signals are involved in preferential inhibition of iNOS over COX-2 gene expression by newly synthesized tetrahydroisoquinoline alkaloid, CKD712, in cells activated with lipopolysaccharide. Cell. Signal. 20:1839–1847.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry of Health & Welfare, Republic of Korea. (A080506) and also supported by MRC program of Ministry of Science and Technology/Korea Science and Engineering Foundation (R13-2005-012-01003-0). Konstantin T and Y.M Ha were supported by BK21 program. We greatly thank Dr. Choi A. M. K. from Harvard Medical School for his commentaries.

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine and Institute of Life Sciences, Biomedical Center (BK21), Gyeongsang National University, Jinju, 660-751, Korea

    Konstantin Tsoyi, Yu Mi Ha, Young Min Kim, Young Soo Lee, Hyo Jung Kim, Hye Jung Kim, Han Geuk Seo, Jae Heun Lee & Ki Churl Chang

Authors
  1. Konstantin Tsoyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Mi Ha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Young Min Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Young Soo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hyo Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hye Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Han Geuk Seo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jae Heun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ki Churl Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ki Churl Chang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tsoyi, K., Ha, Y.M., Kim, Y.M. et al. Activation of PPAR-γ by Carbon Monoxide from CORM-2 Leads to the Inhibition of iNOS but not COX-2 Expression in LPS-Stimulated Macrophages. Inflammation 32, 364–371 (2009). https://doi.org/10.1007/s10753-009-9144-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-009-9144-0

KEY WORDS

Search

Navigation