The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Rhodanthpyrone A and B play an anti-inflammatory role by suppressing the nuclear factor-κB pathway in macrophages

  • Received : 2019.07.15
  • Accepted : 2019.09.10
  • Published : 2019.11.01
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Abstract

Macrophage-associated inflammation is crucial for the pathogenesis of diverse diseases including metabolic disorders. Rhodanthpyrone (Rho) is an active component of Gentiana rhodantha, which has been used in traditional Chinese medicine to treat inflammation. Although synthesis procedures of RhoA and RhoB were reported, the biological effects of the specific compounds have never been explored. In this study, the anti-inflammatory activity and mechanisms of action of RhoA and RhoB were studied in lipopolysaccharide (LPS)-stimulated macrophages. Pretreatment with RhoA and RhoB decreased inducible nitric oxide synthase and cyclooxygenase-2 expressions in RAW 264.7 cells and in thioglycollate-elicited mouse peritoneal macrophages. In addition, it downregulated transcript levels of several inflammatory genes in LPS-stimulated RAW 264.7 cells, including inflammatory cytokines/chemokines (Tnfa, Il6, and Ccl2) and inflammatory mediators (Nos2 and Ptgs2). Macrophage chemotaxis was also inhibited by treatment with the compounds. Mechanistic studies revealed that RhoA and RhoB suppressed the nuclear factor $(NF)-{\kappa}B$ pathway, but not the canonical mitogen activated protein kinase pathway, in LPS-stimulated condition. Moreover, the inhibitory effect of RhoA and RhoB on inflammatory gene expressions was attenuated by treatment with an $NF-{\kappa}B$ inhibitor. Our findings suggest that RhoA and RhoB play an anti-inflammatory role at least in part by suppressing the $NF-{\kappa}B$ pathway during macrophage-mediated inflammation.

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References

  1. Okin D, Medzhitov R. Evolution of inflammatory diseases. Curr Biol. 2012;22:R733-R740. https://doi.org/10.1016/j.cub.2012.07.029
  2. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445-455. https://doi.org/10.1038/nature12034
  3. Schultze JL, Schmieder A, Goerdt S. Macrophage activation in human diseases. Semin Immunol. 2015;27:249-256. https://doi.org/10.1016/j.smim.2015.07.003
  4. de Jesus AA, Canna SW, Liu Y, Goldbach-Mansky R. Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. Annu Rev Immunol. 2015; 33:823-874. https://doi.org/10.1146/annurev-immunol-032414-112227
  5. Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol. 2009;27:693-733. https://doi.org/10.1146/annurev.immunol.021908.132641
  6. Beinke S, Ley SC. Functions of NF-kappaB1 and NF-kappaB2 in immune cell biology. Biochem J. 2004;382(Pt 2):393-409. https://doi.org/10.1042/BJ20040544
  7. Xie QW, Kashiwabara Y, Nathan C. Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem. 1994;269:4705-4708. https://doi.org/10.1016/S0021-9258(17)37600-7
  8. Appleby SB, Ristimaki A, Neilson K, Narko K, Hla T. Structure of the human cyclo-oxygenase-2 gene. Biochem J. 1994;302(Pt 3):723-727. https://doi.org/10.1042/bj3020723
  9. Guha M, Mackman N. LPS induction of gene expression in human monocytes. Cell Signal. 2001;13:85-94. https://doi.org/10.1016/S0898-6568(00)00149-2
  10. Xu M, Zhang M, Wang D, Yang CR, Zhang YJ. Phenolic compounds from the whole plants of Gentiana rhodantha (Gentianaceae). Chem Biodivers. 2011;8:1891-1900. https://doi.org/10.1002/cbdv.201000220
  11. Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell. 2010;142:687-698. https://doi.org/10.1016/j.cell.2010.07.041
  12. Ka SO, Song MY, Bae EJ, Park BH. Myeloid SIRT1 regulates macrophage infiltration and insulin sensitivity in mice fed a high-fat diet. J Endocrinol. 2015;224:109-118. https://doi.org/10.1530/JOE-14-0527
  13. Young Taek H. A concise synthesis of rhodanthpyrone A and B, natural 4-(hydroxyphenyl)-substituted a-pyrones. Nat Prod Commun. 2017;12:95-98.
  14. Wang Z, Ka SO, Han YT, Bae EJ. Dihydropyranoaurone compound damaurone D inhibits LPS-induced inflammation and liver injury by inhibiting NF-${\kappa}B$ and MAPK signaling independent of AMPK. Arch Pharm Res. 2018;41:314-323. https://doi.org/10.1007/s12272-017-1001-3
  15. Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11:738-749. https://doi.org/10.1038/nri3071
  16. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012; 18:363-374. https://doi.org/10.1038/nm.2627
  17. Russo L, Lumeng CN. Properties and functions of adipose tissue macrophages in obesity. Immunology. 2018;155:407-417. https://doi.org/10.1111/imm.13002
  18. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219-246. https://doi.org/10.1146/annurev-physiol-021909-135846
  19. Chi H, Barry SP, Roth RJ, Wu JJ, Jones EA, Bennett AM, Flavell RA. Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses. Proc Natl Acad Sci U S A. 2006;103:2274-2279. https://doi.org/10.1073/pnas.0510965103
  20. Kim HJ, Lee HS, Chong YH, Kang JL. p38 Mitogen-activated protein kinase up-regulates LPS-induced NF-kappaB activation in the development of lung injury and RAW 264.7 macrophages. Toxicology. 2006;225:36-47. https://doi.org/10.1016/j.tox.2006.04.053
  21. Hayden MS, Ghosh S. Regulation of NF-${\kappa}B$ by TNF family cytokines. Semin Immunol. 2014;26:253-266. https://doi.org/10.1016/j.smim.2014.05.004

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