หน้าหลัก

2) The IRF-1 protein might be combined with other transcription factors that bound to the element of the caspase 8 gene promoter. In summary, our studies reveal that the IRF-1 gene is one of the co-up-regulated genes both in GMC induced by sublytic C5b-9 attack (in vitro) and in the renal tissue of Thy-1N (in vivo). Overexpression or knockdown of the IRF-1 gene in GMC could markedly enhance or reduce GMC apoptosis mediated by sublytic C5b-9, respectively, and silencing of the renal IRF-1 gene could effectively attenuate GMC apoptosis and secondary damage of Thy-1N rats. The mechanism of GMC apoptosis upon sublytic C5b-9 is associated with subsequent activation of caspases 8 and 3 followed by IRF-1 overexpression, and IRF-1 significantly up-regulates caspase 8 promoter activity because IRF-1 could bind to the response element (nt 411 to 228) of the caspase 8 promoter, indicating that caspase 8 promoter transcription in response to sublytic C5b-9 is dependent on IRF-1 binding. Additionally, inhibiting caspase 8 and 3 activation mitigates GMC apoptosis of Thy-1N rats. Taken together, these findings implicate that GMC apoptosis is triggered by sublytic C5b-9 in Thy-1N via an IRF-1/caspase 8-dependent mechanism, and IRF-1 induction plays a partially proapoptotic role, which might provide a potential target for treatment of human MsPGN in the future.Acknowledgments--We are grateful to Dr. Li-yuan Yu-Lee and Dr. Fangming Tang for kindly providing the IRF-1 promoter and pGL3basic vector. We also thank Dr. Liwei Lu (Hong Kong University), Guangyong Peng (Saint Louis University), and Ronggen Shi (Nanjing Medical University) for reviewing the manuscript.erative glomerulonephritis. Kidney Int. 49, 335?43 10. Gao, L., Zhang, Y., Qiu, W., Xu, W., Feng, X., Ren, J., Jiang, X., Wang, H., Zhao, D., and Wang, Y. (2009) Effects of PI3K/Akt short hairpin RNA on proliferation, fibronectin production, and synthesis of thrombospondin-1 and transforming growth factor- 1 in glomerular mesangial cells induced by sublytic C5b-9 complexes. Cell Prolif. 42, 83?3 11. Xu, J. H., Qiu, W., Wang, Y. W., Xu, J., Tong, J. X., Gao, L. J., Xu, W. H., and Wu, Y. Q. (2006) Gene expression profile and overexpression of apoptosis-related genes (NGFI-B and Gadd 45 ) in early phase of Thy-1 nephritis model. Cell Tissue Res. 326, 159 ?68 12. Lin, F., Salant, D. J., Meyerson, H., Emancipator, S., Morgan, B. P., and Medof, M. E. (2004) Respective roles of decay-accelerating factor and CD59 in circumventing glomerular injury in acute nephrotoxic serum nephritis. J. Immunol. 172, 2636 ?642 13. Pippin, J. W., Durvasula, R., Petermann, A., Hiromura, K., Couser, W. G., and Shankland, S. J. (2003) DNA damage is a novel response to sublytic complement C5b-9-induced injury in podocytes. J. Clin. Invest. 111, 877?885 14. Qiu, W., Che, N., Feng, X., Xia, M., Wang, H., Zhao, D., and Wang, Y. (2009) Apoptosis of glomerular mesangial cells induced by sublytic C5b-9 complexes in rats with Thy-1 nephritis is dependent on Gadd45 https://britishrestaurantawards.org/members/neck40layer/activity/410024/ upregulation. Eur. J. Immunol. 39, 3251?266 15. Cybulsky, A. V., Takano, T., Papillon, J., Bijian, K., and Guillemette, J. (2005) Activation of the extracellular s.