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ER Stress, P66shc, and P-Akt/Akt Mediate Adjuvant-Induced Inflammation, Which Is Blunted by Argirein, a Supermolecule and Rhein in Rats

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Abstract

We investigated the anti-inflammatory activities of argirein and rhein on inflammatory edema in rat paw which was caused by complete adjuvant, compared with ibuprofen. We hypothesized that the adjuvant-induced inflammation is attributed to upregulation of activating transcript factor 6 (ATF6; a chaperone for endoplasmic reticulum (ER) stress), p66Shc (an adaptive protein modulating oxidative stress), and NADPH oxidase subunits p22phox and gp91phox in the inflamed tissues. Biomarkers were measured in the rat paw in association with monitoring swellings. The primary inflammatory edema of the injected paw occurred rapidly and sustained over a couple of days, and the secondary inflammation developed 2 weeks later. The inflammatory edema was accompanied by upregulation of cytokines including ATF6, p66Shc, p22phox, gp91phox, and MMP-2 and an increase in ratio of p-Akt/Akt in the afflicted paw. These were suppressed by either argirein and rhein or ibuprofen. These findings indicate that ER stress, upregulated p66Shc, and phosphorylated Akt are actively implicated in the inflammatory zone caused by adjuvant injection. These biomarkers were causal factors responsible for inflammation of the afflicted paw and were suppressed by a supermolecule argirein and rhein, and the anti-inflammatory activities of the two compounds were comparable to that of ibuprofen.

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References

  1. Medzhitov, R. 2008. Origin and physiological roles of inflammation. Nature 454: 428–435.

    Article  PubMed  CAS  Google Scholar 

  2. Sweeney, S.E., and G.S. Firestein. 2004. Rheumatoid arthritis: regulation of synovial inflammation. International Journal of Biochemistry and Cell Biology 36: 372–378.

    Article  PubMed  CAS  Google Scholar 

  3. Harirforoosh, S., and F. Jamali. 2009. Renal adverse effects of nonsteroidal anti-inflammatory drugs. Expert Opinion on Drug Safety 8: 669–681.

    Article  PubMed  CAS  Google Scholar 

  4. Sheng, X., M. Wang, M. Lu, B. Xi, H. Sheng, and Y.Q. Zang. 2011. Rhein ameliorates fatty liver disease through negative energy balance, hepatic lipogenic regulation, and immunomodulation in diet-induced obese mice. American Journal of Physiology, Endocrinology and Metabolism 300: E886–E893.

    Article  CAS  Google Scholar 

  5. He, Z.H., R. Zhou, M.F. He, C.B. Lau, G.G. Yue, W. Ge, and P.P. But. 2011. Anti-angiogenic effect and mechanism of rhein from Rhizoma Rhei. Phytomedicine 18: 470–478.

    Article  PubMed  CAS  Google Scholar 

  6. Gao, Q., W.S. Qin, Z.H. Jia, J.M. Zheng, C.H. Zeng, L.S. Li, and Z.H. Liu. 2010. Rhein improves renal lesion and ameliorates dyslipidemia in db/db mice with diabetic nephropathy. Planta Medica 76: 27–33.

    Article  PubMed  CAS  Google Scholar 

  7. Zheng, J.M., J.M. Zhu, L.S. Li, and Z.H. Liu. 2008. Rhein reverses the diabetic phenotype of mesangial cells over-expressing the glucose transporter (GLUT1) by inhibiting the hexosamine pathway. British Journal of Pharmacology 153: 1456–1464.

    Article  PubMed  CAS  Google Scholar 

  8. Boileau, C., S.K. Tat, J.P. Pelletier, S. Cheng, and J. Martel-Pelletier. 2008. Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling. Arthritis Research and Therapy 10: R71.

    Article  PubMed  Google Scholar 

  9. Pasin, J.S., A.P. Ferreira, A.L. Saraiva, V. Ratzlaff, R. Andrighetto, J. Tomazetti, D.S. Avila, S.H. Alves, M.A. Rubin, J. Ferreira, A.R. Santos, and C.F. Mello. 2010. Diacerein decreases TNF-alpha and IL-1beta levels in peritoneal fluid and prevents Baker’s yeast-induced fever in young rats. Inflammation Research 59: 189–196.

    Article  PubMed  CAS  Google Scholar 

  10. Hu, C., X.D. Cong, D.Z. Dai, Y. Zhang, G.L. Zhang, and Y. Dai. 2011. Argirein alleviates diabetic nephropathy through attenuating NADPH oxidase, Cx43, and PERK in renal tissue. Naunyn-Schmiedebergs Archives of Pharmacology 383: 309–319.

    Article  CAS  Google Scholar 

  11. Zhang, G.L., D.Z. Dai, T. Xi, X.D. Cong, Y. Zhang, and Y. Dai. 2011. Isoproterenol-induced FKBP12.6/12 downregulation is modulated by ETA and ETB receptors and reversed by argirhein, a derivative of rhein. Acta Pharmacological Sinica 32: 223–229.

    Article  Google Scholar 

  12. Meyer, D.M., M.I. Jesson, X. Li, M.M. Elrick, C.L. Funckes-Shippy, J.D. Warner, C.J. Gross, M.E. Dowty, S.K. Ramaiah, J.L. Hirsch, M.J. Saabye, J.L. Barks, N. Kishore, and D.L. Morris. 2010. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. Journal of inflammation (Lond) 7: 41.

    Article  Google Scholar 

  13. Staron, A., Makosa, G., and Koter-Michalak, M. 2010. Oxidative stress in erythrocytes from patients with rheumatoid arthritis. Rheumatology International doi:10.1007/s00296-010-1611-2.

  14. Yamasaki, S., N. Yagishita, K. Nishioka, and T. Nakajima. 2007. The roles of synoviolin in crosstalk between endoplasmic reticulum stress-induced apoptosis and p53 pathway. Cell Cycle 6: 1319–1323.

    Article  PubMed  CAS  Google Scholar 

  15. Yin, W., A.P. Signore, M. Iwai, G. Cao, Y. Gao, M.J. Johnnides, R.W. Hickey, and J. Chen. 2007. Preconditioning suppresses inflammation in neonatal hypoxic ischemia via Akt activation. Stroke 38: 1017–1024.

    Article  PubMed  CAS  Google Scholar 

  16. Huang, X.L., J. Xu, X.H. Zhang, B.Y. Qiu, L. Peng, M. Zhang, and H.T. Gan. 2011. PI3K/Akt signaling pathway is involved in the pathogenesis of ulcerative colitis. Inflammation Research 60: 727–734.

    Article  PubMed  CAS  Google Scholar 

  17. Dai, D.Z., J. Huang, L. Su, G.H. Shang, H.D. Xu, D.L. Zhang, and X.Q. Huang. 1991. Antiinflammatory effect on six inflammatory models and antipyretic action of N14. Bulletin of the New Drug Research Foundation 1: 5–13.

    Google Scholar 

  18. Feng, Y., Q. Zhang, D.Z. Dai, H.J. Ying, and Y. Dai. 2007. Strontium fructose 1,6-diphosphate rescues adenine-induced male hypogonadism and upregulates the testicular endothelin-1 system. Clinical and Experimental Pharmacology and Physiology 34: 1131–1137.

    PubMed  CAS  Google Scholar 

  19. Li, N., D.Z. Dai, and Y. Dai. 2008. CPU86017 and its isomers improve hypoxic pulmonary hypertension by attenuating increased ETA receptor expression and extracellular matrix accumulation. Naunyn-Schmiedeberg’s Archives of Pharmacology 378: 541–552.

    Article  PubMed  CAS  Google Scholar 

  20. Bernardi, A., A.C. Zilberstein, E. Jager, M.M. Campos, F.B. Morrone, J.B. Calixto, A.R. Pohlmann, S.S. Guterres, and A.M. Battastini. 2009. Effects of indomethacin-loaded nanocapsules in experimental models of inflammation in rats. British Journal of Pharmacology 158: 1104–1111.

    Article  PubMed  CAS  Google Scholar 

  21. Huang, M.H., S.S. Huang, B.S. Wang, C.H. Wu, M.J. Sheu, W.C. Hou, S.S. Lin, and G.J. Huang. 2011. Antioxidant and anti-inflammatory properties of Cardiospermum halicacabum and its reference compounds ex vivo and in vivo. Journal of Ethnopharmacology 133: 743–750.

    Article  PubMed  CAS  Google Scholar 

  22. Ahmed, A.S., J. Li, M. Ahmed, L. Hua, T. Yakovleva, M.H. Ossipov, G. Bakalkin, and A. Stark. 2010. Attenuation of pain and inflammation in adjuvant-induced arthritis by the proteasome inhibitor MG132. Arthritis and Rheumatism 62: 2160–2169.

    PubMed  CAS  Google Scholar 

  23. Hah, Y.S., Y.R. Lee, J.S. Jun, H.S. Lim, H.O. Kim, Y.G. Jeong, G.M. Hur, S.Y. Lee, M.J. Chung, J.W. Park, S.I. Lee, and B.H. Park. 2010. A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritis. Arthritis and Rheumatism 62: 2313–2321.

    Article  PubMed  CAS  Google Scholar 

  24. Cheng, A.W., T.V. Stabler, M. Bolognesi, and V.B. Kraus. 2011. Selenomethionine inhibits IL-1beta inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) expression in primary human chondrocytes. Osteoarthritis and Cartilage 19: 118–125.

    Article  PubMed  CAS  Google Scholar 

  25. Busso, N., A. So, V. Chobaz-Peclat, C. Morard, E. Martinez-Soria, D. Talabot-Ayer, and C. Gabay. 2002. Leptin signaling deficiency impairs humoral and cellular immune responses and attenuates experimental arthritis. Journal of Immunology 168: 875–882.

    CAS  Google Scholar 

  26. Wong, Y.F., H. Zhou, J.R. Wang, Y. Xie, H.X. Xu, and L. Liu. 2008. Anti-inflammatory and analgesic effects and molecular mechanisms of JCICM-6, a purified extract derived from an anti-arthritic Chinese herbal formula. Phytomedicine 15: 416–426.

    Article  PubMed  CAS  Google Scholar 

  27. Griffiths, H.R. 2005. ROS as signalling molecules in T cells—evidence for abnormal redox signalling in the autoimmune disease, rheumatoid arthritis. Redox Report 10: 273–280.

    Article  PubMed  CAS  Google Scholar 

  28. Valvason, C., E. Musacchio, A. Pozzuoli, R. Ramonda, R. Aldegheri, and L. Punzi. 2008. Influence of glucosamine sulphate on oxidative stress in human osteoarthritic chondrocytes: effects on HO-1, p22(Phox) and iNOS expression. Rheumatology 47: 31–35.

    Article  PubMed  CAS  Google Scholar 

  29. Remans, P.H., M. van Oosterhout, T.J. Smeets, M. Sanders, W.M. Frederiks, K.A. Reedquist, P.P. Tak, F.C. Breedveld, and J.M. van Laar. 2005. Intracellular free radical production in synovial T lymphocytes from patients with rheumatoid arthritis. Arthritis and Rheumatism 52: 2003–2009.

    Article  PubMed  CAS  Google Scholar 

  30. Skurlova, M., A. Stofkova, and J. Jurcovicova. 2011. Anxiety-like behavior in the elevated-plus maze tests and enhanced IL-1beta, IL-6, NADPH oxidase-1, and iNOS mRNAs in the hippocampus during early stage of adjuvant arthritis in rats. Neuroscience Letters 487: 250–254.

    Article  PubMed  CAS  Google Scholar 

  31. Peng, H.J., D.Z. Dai, H. Ji, and Y. Dai. 2010. The separate roles of endothelin receptors participate in remodeling of matrix metalloproteinase and connexin 43 of cardiac fibroblasts in maladaptive response to isoproterenol. European Journal of Pharmacology 634: 101–106.

    Article  PubMed  CAS  Google Scholar 

  32. Wehling, N., G.D. Palmer, C. Pilapil, F. Liu, J.W. Wells, P.E. Muller, C.H. Evans, and R.M. Porter. 2009. Interleukin-1beta and tumor necrosis factor alpha inhibit chondrogenesis by human mesenchymal stem cells through NF-kappaB-dependent pathways. Arthritis and Rheumatism 60: 801–812.

    Article  PubMed  CAS  Google Scholar 

  33. Koskinen, A., K. Vuolteenaho, R. Nieminen, T. Moilanen, and E. Moilanen. 2011. Leptin enhances MMP-1, MMP-3 and MMP-13 production in human osteoarthritic cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients. Clinical and Experimental Rheumatology 29: 57–64.

    PubMed  Google Scholar 

  34. Lee, E.G., S.L. Lee, H.J. Chae, S.J. Park, Y.C. Lee, and W.H. Yoo. 2010. Ethyl acetate fraction from Cudrania tricuspidata inhibits IL-1beta-induced rheumatoid synovial fibroblast proliferation and MMPs, COX-2 and PGE2 production. Biological Research 43: 225–231.

    Article  PubMed  Google Scholar 

  35. Fujimura, M., M. Watanabe, H. Shimizu, and T. Tominaga. 2007. Expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) in cerebral cavernous malformations: immunohistochemical analysis of MMP-2, -9 and TIMP-2. Acta Neurochirurgica 149: 179–183. discussion 183.

    Article  PubMed  CAS  Google Scholar 

  36. Feelisch, M. 2008. The chemical biology of nitric oxide-an outsider’s reflections about its role in osteoarthritis. Osteoarthritis and Cartilage 16(Suppl 2): S3–S13.

    Article  PubMed  Google Scholar 

  37. Ogata, H., T. Takahashi, K. Ishikawa, T. Ishibashi, Y. Maruyama, M. Watanabe, and K. Edo. 2010. Effects of oral supplementation of L-arginine in the treatment of pulmonary hypertension secondary to pulmonary embolism: a case report. Fukushima Journal of Medical Science 56: 135–138.

    Article  PubMed  Google Scholar 

  38. Rota, M., N. LeCapitaine, T. Hosoda, A. Boni, A. De Angelis, M.E. Padin-Iruegas, G. Esposito, S. Vitale, K. Urbanek, C. Casarsa, M. Giorgio, T.F. Luscher, P.G. Pelicci, P. Anversa, A. Leri, and J. Kajstura. 2006. Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circulation Research 99: 42–52.

    Article  PubMed  CAS  Google Scholar 

  39. Giorgio, M., E. Migliaccio, F. Orsini, D. Paolucci, M. Moroni, C. Contursi, G. Pelliccia, L. Luzi, S. Minucci, M. Marcaccio, P. Pinton, R. Rizzuto, P. Bernardi, F. Paolucci, and P.G. Pelicci. 2005. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122: 221–233.

    Article  PubMed  CAS  Google Scholar 

  40. Pagnin, E., G. Fadini, R. de Toni, A. Tiengo, L. Calo, and A. Avogaro. 2005. Diabetes induces p66shc gene expression in human peripheral blood mononuclear cells: relationship to oxidative stress. Journal of Clinical Endocrinology and Metabolism 90: 1130–1136.

    Article  PubMed  CAS  Google Scholar 

  41. Almeida, M., L. Han, E. Ambrogini, S.M. Bartell, and S.C. Manolagas. 2010. Oxidative stress stimulates apoptosis and activates NF-kappaB in osteoblastic cells via a PKCbeta/p66shc signaling cascade: counter regulation by estrogens or androgens. Molecular Endocrinology 24: 2030–2037.

    Article  PubMed  CAS  Google Scholar 

  42. Li, G., C. Scull, L. Ozcan, and I. Tabas. 2010. NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis. The Journal of Cell Biology 191: 1113–1125.

    Article  PubMed  CAS  Google Scholar 

  43. Nakajima, S., N. Hiramatsu, K. Hayakawa, Y. Saito, H. Kato, T. Huang, J. Yao, A.W. Paton, J.C. Paton, and M. Kitamura. 2011. Selective abrogation of BiP/GRP78 blunts activation of NF-kappaB through the ATF6 branch of the UPR: involvement of C/EBPbeta and mTOR-dependent dephosphorylation of Akt. Molecular and Cellular Biology 31: 1710–1718.

    Article  PubMed  CAS  Google Scholar 

  44. Bozulic, L., and B.A. Hemmings. 2009. PIKKing on PKB: regulation of PKB activity by phosphorylation. Current Opinion in Cell Biology 21: 256–261.

    Article  PubMed  CAS  Google Scholar 

  45. Yang, W.L., J. Wang, C.H. Chan, S.W. Lee, A.D. Campos, B. Lamothe, L. Hur, B.C. Grabiner, X. Lin, B.G. Darnay, and H.K. Lin. 2009. The E3 ligase TRAF6 regulates Akt ubiquitination and activation. Science 325: 1134–1138.

    Article  PubMed  CAS  Google Scholar 

  46. Terabe, F., M. Kitano, M. Kawai, Y. Kuwahara, T. Hirano, J. Arimitsu, K. Hagihara, Y. Shima, M. Narazaki, T. Tanaka, I. Kawase, H. Sano, and A. Ogata. 2009. Imatinib mesylate inhibited rat adjuvant arthritis and PDGF-dependent growth of synovial fibroblast via interference with the Akt signaling pathway. Modern Rheumatology 19: 522–529.

    Article  PubMed  CAS  Google Scholar 

  47. Hamamdzic, D., R.S. Fenning, D. Patel, E.R. Mohler 3rd, K.A. Orlova, A.C. Wright, R. Llano, M.G. Keane, R.P. Shannon, M.J. Birnbaum, and R.L. Wilensky. 2010. Akt pathway is hypoactivated by synergistic actions of diabetes mellitus and hypercholesterolemia resulting in advanced coronary artery disease. American Journal of Physiology Heart Circulatory Physiology 299: H699–H706.

    Article  CAS  Google Scholar 

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Acknowledgments

This work was supported by National Key New Drug Innovation Program of China no. 2009ZX09308 and the National Natural Science Foundation of China no. 81070145.

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Authors and Affiliations

  1. Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Xiao-Dong Cong, Ming-Jian Ding, You Wu & Yun Zhang

  2. Research Division of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China

    De-Zai Dai & Yin Dai

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  1. Xiao-Dong Cong
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Correspondence to De-Zai Dai.

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Xiao-Dong Cong and Ming-Jian Ding have made equal contributions to the paper.

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Cong, XD., Ding, MJ., Dai, DZ. et al. ER Stress, P66shc, and P-Akt/Akt Mediate Adjuvant-Induced Inflammation, Which Is Blunted by Argirein, a Supermolecule and Rhein in Rats. Inflammation 35, 1031–1040 (2012). https://doi.org/10.1007/s10753-011-9407-4

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