Effect of Chelerythrine Against Endotoxic Shock in Mice and Its Modulation of Inflammatory Mediators in Peritoneal Macrophages Through the Modulation of Mitogen-Activated Protein Kinase (MAPK) Pathway
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A quaternary benzo [c] alkaloid chelerythrine (CHE), which is a traditional herbal prescription, has been used for the treatment of various inflammatory diseases. To gain insight into the anti-inflammatory effect and molecular mechanisms underlying the anti-inflammatory activity of CHE, we used experimentally induced mice endotoxic shock moled and lipopolysaccharide (LPS)-induced murine peritoneal macrophages to examine the anti-inflammatory function of CHE. CHE displayed significant anti-inflammatory effects in experimentally induced mice endotoxic shock model in vivo through inhibition of LPS-induced tumor necrosis factor-alpha (TNF-α) level and nitric oxide (NO) production in serum. Additionally, our data suggest that CHE treatment inhibits LPS-induced TNF-α level and NO production in LPS-induced murine peritoneal macrophages through selective inhibition of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activation. Moreover, the effects of CHE on NO and cytokine TNF-α production can possibly be explained by the role of p38 MAPK and ERK1/2 in the regulation of inflammatory mediators expression.
KEY WORDSchelerythrine anti-inflammatory effect nitric oxide TNF-α mitogen-activated protein kinase
This work was supported by a research grant from Xi'an Jiaotong University.
Conflict of interest
The authors declare no competing financial interests.
- 1.Walterova, D., J.U. lrichova, I. Valka, J. Vicar, C. Vavreckova, E. Taborska, R.J. Harkrader, D.L. Meyer, H. Cerna, and V. Simanek. 1995. Benzo [c] phenanthridine alkaloids sanguinarine and chelerythrine: biological activities and dental care applications. Acta Universitatis Palackianae Olomucensis Facultatis Medicae 139: 7–16.PubMedGoogle Scholar
- 6.Vogt, A., A. Tamewitz, J. Skoko, R.P. Sikorski, K.A. Giuliano, and J.S. Lazo. 2005. The benzo[c]phenanthridine alkaloid, sanguinarine, is a selective, cell-active inhibitor of mitogen-activated protein kinase phosphatase-1. Journal of Biological Chemistry 280: 19078–19086.PubMedCrossRefGoogle Scholar
- 8.Herbert, J.M., P. Savi, M.C. Laplace, A. Dumas, and F. Dol. 1993. Chelerythrine, a selective protein kinase C inhibitor, counteracts pyrogen-induced expression of tissue factor without effect on thrombomodulin down-regulation in endothelial cells. Thrombosis Research 71(6): 487–493.PubMedCrossRefGoogle Scholar
- 11.Nathan, C. 1992. Nitric oxide as a secretory product of mammalian cells. The FASEB Journal 6: 3051–3064.Google Scholar
- 14.Nagai, H., H. Kumamoto, M. Fukuda, and T. Takahashi. 2003. Inducible nitric oxide synthase and apoptosis-related factors in the synovial tissues of temporomandibular joints with internal derangement and osteoarthritis. Journal of Oral and Maxillofacial Surgery 61: 801–807.PubMedCrossRefGoogle Scholar
- 17.Morrison, D.C., R.L. Danner, C.A. Dinarello, R.S. Munford, C. Natanson, and M. Pollack. 1994. Bacterial endotoxins and pathogenesis of Gram-negative infections: current status and future direction. Journal of Endotoxin Research 1: 71–83.Google Scholar
- 20.Di Santo, E., M. Sironi, P. Pozzi, P. Gnocchi, A.M. Isetta, A. Delvaux, M. Goldman, A. Marchant, and P. Ghezzi. 1995. Interleukin-10 inhibits lipopolysaccharide-induced tumor necrosis factor and interleukin-1β production in the brain without affecting the activation of the hypothalamus–pituitary adrenal axis. Neuroimmunomodulation 2: 149–154.PubMedCrossRefGoogle Scholar
- 22.De Stefano, D., M.C. Maiuri, B. Iovine, A. Ialenti, M.A. Bevilacqua, and R. Carnuccio. 2006. The role of NF-kappa B, IRF-1, and STAT-1 alpha transcription factors in the iNOS gene induction by gliadin and IFN-gamma in RAW 264.7 macrophages. Journal of Molecular Medicine 84: 65–74.PubMedCrossRefGoogle Scholar
- 25.Chen, T.H., Y.C. Kao, B.C. Chen, C.H. Chen, P. Chan, and H.M. Lee. 2006. Dipyridamole activation of mitogen-activated protein kinase phosphatase-1 mediates inhibition of lipopolysaccharide-induced cyclooxygenase-2 expression in RAW 264.7 cells. European Journal of Pharmacology 541: 138–146.PubMedCrossRefGoogle Scholar
- 28.Ajizian, S.J., B.K. English, and E.A. Meals. 1999. Specific inhibitors of p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways block inducible nitric oxide synthase and tumor necrosis factor accumulation in murine macrophages stimulated with lipopolysaccharide and interferon gamma. Journal of Infectious Diseases 179: 939–944.PubMedCrossRefGoogle Scholar
- 36.Murakami, A., D. Takahashi, K. Hagihara, K. Koshimizu, and H. Ohigashi. 2003. Combinatorial effects of nonsteroidal anti-inflammatory drugs and food constituents on production of prostaglandin E2 and tumor necrosis factor alpha in RAW264.7 murine macrophages. Bioscience, Biotechnology, and Biochemistry 67: 1056–1062.PubMedCrossRefGoogle Scholar
- 47.Jaramillo, M., P.H. Naccache, and M. Olivier. 2004. Monosodium urate crystals synergize with IFN-gamma to generate macrophage nitric oxide involvement of extracellular signal-regulated kinase 1/2 and NF-kappa B. Journal of Immunology 172: 5734–5742.Google Scholar