Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with various clinical manifestations affecting different tissues. Pro-inflammatory cytokines, such as interleukin 1β, IL-6 and IFN-g are associated with the SLE progression; however, the precise molecular mechanisms that in occurs improper cytokines production in SLE remain unknown. Autoantibody production and renal disease were evaluated in NZB/W F1 mice treated with a specific Pin1 inhibitor, Juglone. Inhibition of Pin1 activity significantly suppressed the IL-6 expression in NZB/W F1 mice and developed milder renal lesions than the lesions developing in non Juglone-treated mice. We further found that Pin1 inhibitor treatment suppresses B-cell differentiation and T-cell activation in NZB/W F1 lupus mice. Finally, stat3 phosphorylation was decreased in T cells from Pin1inhibitor-treated mice at 40 weeks of age as compared to that from the saline and isotype control mAb treatment groups. This is the first study to demonstrate that Pin1 plays critical roles in SLE development. Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy target for future SLE therapies.
Keywords: Pin1; SLE; IL-6; Auto-antibody; Cytokine
Copyright © 2015 by The American Society for BioMedicine and BM-Publisher, Inc.
- Livingston B, Bonner A, Pope J. Differences in clinical manifestations between childhood-onset lupus and adult-onset lupus: a meta-analysis. Lupus 2011;20(13):1345-55.
- Cooper GS, Dooley MA, Treadwell EL, et al. Hormonal, environmental, and infectious risk factors for developing systemic lupus erythematosus. Arthritis Rheum 1998;41(10):1714-24.
- Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008; 358(9):929-39.
- Cancro MP, D'Cruz DP, Khamashta MA. The role of B lymphocyte stimulator (BLyS) in systemic lupus erythematosus. J Clin Invest 2009;119(5):1066-73.
- Bosch X. Systemic lupus erythematosus and the neutrophil. N Engl J Med 2011; 365(8):758-60.
- Hu W, Ren H. A meta-analysis of the association of IRF5 polymorphism with systemic lupus erythematosus. Int J Immunogenet 2011;38(5):411-7.
- Long AA, Ginsberg JS, Brill-Edwards P, et al. The relationship of antiphospholipid antibodies to thromboembolic disease in systemic lupus erythematosus: a cross-sectional study. Thromb Haemost 1991;66(5):520-4.
- Kishimoto T. Interleukin-6: from basic science to medicine - 40 years in immunology. Annu Rev Immunol 2005;23:1-21.
- Mihara M, Nishimoto N, Ohsugi Y. The therapy of autoimmune diseases by anti-interleukin-6 receptor antibody. Expert Opin Biol Ther 2005;5:683-90. https://doi.org/10.1517/147125184.108.40.2063
- Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis. Roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 1998;161:6480-6.
- Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;65:521-30.
- Ishihara K, Hirano T. IL-6 in autoimmune disease and chronic inflammatory proliferative disease. Cytokine Growth Factor Rev 2002;13:357-68.
- Hagihara K, Nishikawa T, Isobe T, Song J, Sugamata Y, Yoshizaki K. IL-6 plays a critical role in the synergistic induction of human serum amyloid A (SAA) gene when stimulated with proinflammatory cytokines as analyzed with an SAA isoform real-time quantitative RT-PCR assay system. Biochem Biophys Res Comms 2003;314: 363-9.
- Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-8.
- Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y. IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 1998;161:6480-6486.
- Sun KH, Yu CL, Tang SJ, Sun GH. Monoclonal anti-double-stranded DNA autoantibody stimulates the expression and release of IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha from normal human mononuclear cells involving in the lupus pathogenesis. Immunology 2000; 99:352-360.
- Iwano M, Dohi K, Hirata E, et al. Urinary levels of IL-6 in patients with active lupus nephritis. Clin Nephrol 1993;40:16-21.
- Herrera-Esparza R, Barbosa-Cisneros O, Villalobos-Hurtado R, Avalos-Diaz E. Renal expression of IL-6 and TNFalpha genes in lupus nephritis. Lupus 1998;7:154-158.
- Malide D, Russo P, Bendayan M. Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients. Hum Pathol 1995;26:558- 564.
- Kuroiwa T, Lee EG, Danning CL, Illei GG, McInnes IB, Boumpas DT. CD40 ligand-activated human monocytes amplify glomerular inflammatory responses through soluble and cell-to-cell contact-dependent mechanisms. J Immunol 1999;163:2168-2175.
- Yun Y, Zheng X, Chen L, et al. Expression of ATF3 in mouse protects the liver against sepsis via inhibiting HMGB expression. American journal of BioMedicine 2014;2(3):337-349. https://doi.org/10.18081/2333-5106/014-04/288-299
- Bayer E, Goettsch S, Mueller JW, et al. Structural analysis of the mitotic regulator hPin1 in solution: insights into domain architecture and substrate binding. J. Biol. Chem 2003;278:26183-26193.
- Zhou XZ, Kops O, Werner A, et al. Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins. Mol. Cell 2000;6:873-883. https://doi.org/10.1016/S1097-2765(05)00083-3
- Bao L, Sauter G, Sowadski J, Lu KP, Wang D. Prevalent overexpression of prolyl isomerase Pin1 in human cancers. Am. J. Pathol 2004;164:1727-1737.
- Yousif NG. Fibronectin promotes migration and invasion of ovarian cancer cells through up-regulation of FAK-PI3K/Akt pathway. Cell Biol Int 2014; 38(1):85-91.
- Hennig L, Christner C, Kipping M, et al. Selective inactivation of parvulin-like peptidyl-prolylcis/trans isomerases by juglone. Biochemistry 1998; 37: 5953-5960.
- Dourlen P, Ando K, Hamdane M, et al. The peptidyl prolyl cis/trans isomerase Pin1 down-regulates the inhibitor of apoptosis protein survivin. Biochim. Biophys. Acta 2007; 1773: 1428-1437.
- Wang XJ, Xu B, Mullins AB, Neiler FK, Etzkorn FA. Conformationally locked isostere of phosphoSer-cis-Pro inhibits Pin1 23-fold better than phosphoSer-trans-Pro isostere. J. Am. Chem. Soc. 2004;126:15533-15542.
- WA Everett WA, L Ao, JC Cleveland, et al. Ghrelin reduces myocardial injury following global ischemia and reperfusion via suppression of myocardial inflammatory response. American journal of BioMedicine 2013;1(2):38-48
- Shen ZJ, Esnault S, Rosenthal LA, et al. Pin1 regulates TGF-β1 production by activated human and murine eosinophils and contributes to allergic lung fibrosis. J. Clin. Invest 2008;118:479-490.
- Ryo A, Suizu F, Yoshida Y, et al. Regulation of NF-κB signaling by Pin1-dependent prolyl isomerization and ubiquitin-mediated proteolysis of p65/RelA. Mol. Cell 2003; 12:1413-1426.
- Lim J, Balastik M, Lee T H, et al. Pin1 has opposite effects on wild-type and P301L Tau stability and tauopathy. J. Clin. Invest 2008; 118: 1877-1889.
- Kim MR, Choi HK, Cho KB, Kim HS, Kang KW. Involvement of Pin1 induction in epithelial-mesenchymal transition of tamoxifen-resistant breast cancer cells. Cancer Sci 2009;100:18341841.
- Lu KP. Prolyl isomerase Pin1 as a molecular target for cancer diagnostics and therapeutics. Cancer Cell 2003;4:175-180.
- Lee TH, Pastorino L, Lu KP. Peptidyl-prolyl cis-trans isomerase Pin1 in ageing, cancer, and Alzheimer disease. Expert Rev. Mol. Med 2011;13:e21. [PubMed]
- Yeh ES, Means AR. PIN1, the cell cycle and cancer. Nat. Rev. Cancer 2007;7:381-388.
- Lu KP, Hanes SD, Hunter T. A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 1996;380:544-547.
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American Journal of BioMedicine 2015, Volume 3, Issue 2, pages 139-152
Received February 10, 2015; Accepted May; 29, 2015, Published June 27, 2015
How to cite this article
Takeno MR, Gunn JB, Suzuki JT, et al. A novel role of peptidyl-prolyl isomerase-1 as inducer of IL-6 expression in systemic lupus erythematosus. American Journal of BioMedicine 2015;3(2):139-152