Baicalin Ameliorates Dysimmunoregulation in Pristane-Induced Lupus Mice: Production of IL-6 and $PGE_2$ and Activation of T cells

  • Received : 2011.10.06
  • Accepted : 2011.12.05
  • Published : 2011.12.30

Abstract

Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease characterized by abnormalities in T cell immunoregulation and hyperreactivity of B cells, leading to autoantibody production and multiorgan injuries. We investigated the effect of baicalin on aberrant immunoregulation in pristane-induced lupus mice. Mice received i.p. a single injection of 0.5 ml of pristane or PBS, and approximately 3 months later, were used as a pristane-induced lupus model or healthy controls. The pristane-induced lupus mice and healthy mice were randomly divided into three groups: healthy mouse group (healthy control), pristane-primed lupus control group (lupus control), and baicalin (BAC)-treated pristane-primed lupus mouse group (BAC-treated lupus). The pristane-induced lupus mice and healthy mice were administrated orally with BAC 50 mg/kg or PBS once in a day for 10 ds. These results demonstrated that levels of serum IL-6, LPS-induced production of IL-6, $PGE_2$ and NO by macrophages, $PGE_2$-stimulated production of IL-6 by macrophages and IFN-${\gamma}$ by thymocytes, and an overexpression of splenic NKT cells and CD69+CD4+ T cells were downregulated in BAC-treated lupus compared to lupus control, while reduced apoptosis of splenic CD4+ T cells were upregulated. Therefore, these findings suggest that BAC may attenuate autoimmunity and disease activity in lupus via downregulation of aberrant activation of T cells and inhibition of overproduction of IL-6 and $PGE_2$ in pristane-induced lupus mice.

Keywords

References

  1. Akaogi, J., Nozaki, T., Satoh, M., and Yamada, H., Role of $PGE_2$ and EP receptors in the pathogenesis of rheumatoid arthritis and as a novel therapeutic strategy. Endocr. Metab. Immune. Disord. Drug Targets 6, 383-394 (2006). https://doi.org/10.2174/187153006779025711
  2. Balomenos, D., Rumold, R., and Theofilopoulos, A.N., Interferon-gamma is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J. Clin. Invest. 101, 364-371 (1998). https://doi.org/10.1172/JCI750
  3. Chae, B.S. and Shin, T.Y., Immunoregulatory abnormalities of T cells and hyperreactivity of B cells in the in vitro immune response in pristane-induced lupus mice. Arch. Pharm. Res. 30, 191-198 (2007). https://doi.org/10.1007/BF02977694
  4. Chae, B.S., Shin, T.Y., Kim, D.K., Eun, J.S., Leem, J.Y., and Yang, J.H., Prostaglandin $E_2$-mediated dysregulation of proinflammatory cytokine production in pristane-induced lupus mice. Arch. Pharm. Res. 31, 503-510 (2008). https://doi.org/10.1007/s12272-001-1185-6
  5. Chae, B.S., Shin, T.Y., Oh, C.H., Kim, D.K., Eun, J.S., Jeon, H., Park, J.S., Kim, M.S., and Yang, J.H., Regulatory effect of Scutellariae radix on the proinflammatory cytokine production and abnormal T-cell activation in vitro in pristane-induced lupus mice. Nat. Prod. Sci. 13, 207-213 (2007).
  6. Chen, Y.C., Shen, S.C., Chen, L.G., Lee, T.J., and Yang, L.L., Wogonin, baicalin, and baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expressions induced by nitric oxide synthase inhibitors and lipopolysaccharide. Biochem. Pharmacol. 61, 1417-1427 (2001). https://doi.org/10.1016/S0006-2952(01)00594-9
  7. Chun, H.Y., Chung, J.W., Kim, H.A., Yun, J.M., Jeon, J.Y., Ye, Y.M., Kim, S.H., Park, H.S., and Suh, C.H., Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J. Clin. Immunol. 27, 461-466 (2007). https://doi.org/10.1007/s10875-007-9104-0
  8. Crispin, J.C., Martinez, A., de Pablo, P., Velasquillo, C., and Alcocer-Varela, J., Participation of the CD69 antigen in the T-cell activation process of patients with systemic lupus erythematosus. Scand. J. Immunol. 48, 196-200 (1998). https://doi.org/10.1046/j.1365-3083.1998.00366.x
  9. Davas, E.M., Tsirogianni, A., Kappou, I., Karamitsos, D., Economidou, I., and Dantis, P.C., Serum IL-6, TNFalpha, p55 srTNFalpha, p75srTNFalpha, srIL-2alpha levels and disease activity in systemic lupus erythematosus. Clin. Rheumatol. 18, 17-22 (1999). https://doi.org/10.1007/s100670050045
  10. Dean, G.S., Tirrell-Price, J., Crawley, E., and Isenberg, D.A., Cytokines and systemic lupus erythematosus. Ann. Rheum. Dis. 59, 243-251 (2000). https://doi.org/10.1136/ard.59.4.243
  11. Gao, Z., Huang, K., Yang, X., and Xu, H., Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi. Biochim. Biophys. Acta. 1472, 643-650 (1999). https://doi.org/10.1016/S0304-4165(99)00152-X
  12. Haas, C., Ryffel, B., and Le Hir, M., IFN-gamma receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZB ${\times}$ NZW)F1 mice. J. Immunol. 160, 3713-3718 (1998).
  13. Hao, H., Gufu, H., Lei, F., Dang, L., and Zhongliang, Y., Baicalin suppresses expression of TLR2/4 and NF-B in chlamydia trachomatis-infected mice. Immunopharmacol. Immunotoxicol. 2011 May 26.
  14. Herrera-Acosta, J., Reyes, P.A., Lopez Manay, G., Padilla, L., Cerdas Calderon, M., Ruiz, A., and Perez Grovas, H., Inhibition of prostaglandin synthesis results in suppression of renal functional reserve in lupus nephritis. Rev. Invest. Clin. 39, 107-114 (1987).
  15. Hinson, R.M., Williams, J.A., and Shacter, E., Elevated interleukin 6 is induced by prostaglandin $E_2$ in a murine model of inflammation: possible role of cyclooxygenase-2. Proc. Natl. Acad. Sci. U S A 93, 4885-4890 (1996). https://doi.org/10.1073/pnas.93.10.4885
  16. Hoffman, R.W., T cells in the pathogenesis of systemic lupus erythematosus. Clin. Immunol. 113, 4-13 (2004). https://doi.org/10.1016/j.clim.2004.05.001
  17. Ishikawa, S., Akakura, S., Abe, M., Terashima, K., Chijiiwa, K., Nishimura, H., Hirose, S., and Shirai, T., A subset of CD4+ T cells expressing early activation antigen CD69 in murine lupus: possible abnormal regulatory role for cytokine imbalance. J. Immunol. 161, 1267-1273 (1998).
  18. Kyttaris, V.C., Juang, Y.T., and Tsokos, G.C., Immune cells and cytokines in systemic lupus erythematosus: an update. Curr. Opin. Rheumatol. 17, 518-522 (2005). https://doi.org/10.1097/01.bor.0000170479.01451.ab
  19. Liang, B., Gardner, D.B., Griswold, D.E., Bugelski, P.J., and Song, X.Y., Anti-interleukin-6 monoclonal antibody inhibits autoimmune responses in a murine model of systemic lupus erythematosus. Immunology 119, 296-305 (2006). https://doi.org/10.1111/j.1365-2567.2006.02433.x
  20. Li-Weber, M., New therapeutic aspects of flavones: the anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat. Rev. 35, 57-68 (2009). https://doi.org/10.1016/j.ctrv.2008.09.005
  21. Mendiratta, S.K., Martin, W.D., Hong, S., Boesteanu, A., Joyce, S., and Van Kaer, L., CD1d1 mutant mice are deficient in natural T cells that promptly produce IL-4. Immunity 6, 469-477 (1997). https://doi.org/10.1016/S1074-7613(00)80290-3
  22. Nagy, G., Koncz, A., and Perl, A., T- and B-cell abnormalities in systemic lupus erythematosus. Crit. Rev. Immunol. 25, 123-140 (2005). https://doi.org/10.1615/CritRevImmunol.v25.i2.30
  23. Oates, J.C. and Gilkeson, G.S., The biology of nitric oxide and other reactive intermediates in systemic lupus erythematosus. Clin. Immunol. 121, 243-250 (2006). https://doi.org/10.1016/j.clim.2006.06.001
  24. Portales-Perez, D., Gonzalez-Amaro, R., Abud-Mendoza, C., and Sanchez-Armass, S., Abnormalities in CD69 expression, cytosolic pH and $Ca^{2+}$ during activation of lymphocytes from patients with systemic lupus erythematosus. Lupus 6, 48-56 (1997). https://doi.org/10.1177/096120339700600107
  25. Reininger, L., Santiago, M.L., Takahashi, S., Fossati, L., and Izui, S., T helper cell subsets in the pathogenesis of systemic lupus erythematosus. Ann. Med. Interne. (Paris) 147, 467-471 (1996).
  26. Richards, H.B., Satoh, M., Shaw, M., Libert, C., Poli, V., and Reeves, W.H., Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. J. Exp. Med. 188, 985-990 (1998). https://doi.org/10.1084/jem.188.5.985
  27. Satoh, M. and Reeves, W. H., Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane. Exp. Med. 180, 2341-2346 (1994). https://doi.org/10.1084/jem.180.6.2341
  28. Shacter, E., Arzadon, G.K., and Williams, J., Elevation of interleukin-6 in response to a chronic inflammatory stimulus in mice: inhibition by indomethacin. Blood 80, 194-202 (1992).
  29. Stasiuk, L.M., Ghoraishian, M., Elson, C.J., and Thompson, S.J., Pristane-induced arthritis is CD4+ T-cell dependent. Immunology 90, 81-86 (1997). https://doi.org/10.1046/j.1365-2567.1997.00121.x
  30. Takahashi, T. and Strober, S., Natural killer T cells and innate immune B cells from lupus-prone NZB/W mice interact to generate IgM and IgG autoantibodies. Eur. J. Immunol. 38(1), 156-165 (2008). https://doi.org/10.1002/eji.200737656
  31. Takeno, M., Nagafuchi, H., Kaneko, S., Wakisaka, S., Oneda, K., Takeba, Y., Yamashita, N., Suzuki, N., Kaneoka, H., and Sakane, T., Autoreactive T cell clones from patients with systemic lupus erythematosus support polyclonal autoantibody production. J. Immunol. 158, 3529-3538 (1997).
  32. Takeuchi, T., Tsuzaka, K., Abe, T., Yoshimoto, K., Shiraishi, K., Kameda, H., and Amano, K., T cell abnormalities in systemic lupus erythematosus. Autoimmunity 38, 339-346 (2005). https://doi.org/10.1080/08916930500123983
  33. Theofilopoulos, A.N., Koundouris, S., Kono, D.H., and Lawson, B.R., The role of IFN-gamma in systemic lupus erythematosus: a challenge to the Th1/Th2 paradigm in autoimmunity. Arthritis Res. 3, 136-141 (2001). https://doi.org/10.1186/ar290
  34. Tsai, C.Y., Wu, T.H., Tsai, S.T., Chen, K.H., Thajeb, P., Lin, W.M., Yu, H.S., and Yu, C.L., Cerebrospinal fluid interleukin-6, prostaglandin $E_2$ and autoantibodies in patients with neuropsychiatric systemic lupus erythematosus and central nervous system infections. Scand. J. Rheumatol. 23, 57-63 (1994). https://doi.org/10.3109/03009749409103028
  35. Xu, J., Huang, R., Yang, Y.J., Jin, S.J., and Zhang, J.F., Effects of baicalin on apoptosis in rats with autoimmune encephalomyelitis. Zhongguo Dang Dai Er Ke Za Zhi 13, 665-668 (2011).
  36. Xu, L., Zhang, L., Yi, Y., Kang, H.K., and Datta, S.K., Human lupus T cells resist inactivation and escape death by upregulating COX-2. Nat. Med. 10, 411-415 (2004). https://doi.org/10.1038/nm1005
  37. Zeng, D., Liu, Y., Sidobre, S., Kronenberg, M., and Strober, S., Activation of natural killer T cells in NZB/W mice induces Th1-type immune responses exacerbating lupus. J. Clin. Invest. 112, 1211-1222 (2003). https://doi.org/10.1172/JCI200317165