1. ��ɽ��ѧ�����ڶ�ҽԺƤ����
2.
3. ��������ɽ��ѧ�ڶ�����ҽԺƤ����

PI3K/AKT�ź�ͨ·��ϸ������Ҫ���źŴ���ͨ·֮һ��ͨ��Ӱ�����ζ���ЧӦ���ӵĻ����ϸ���Ļ������ܣ��������桢��������ֳ�ʹ�л�������о����֣�T��B�ܰ�ϸ��PI3K/AKT�ź�ͨ·���쳣���SLE�������ߵķ�����չ������ء�����PI3K/AKT�ź�ͨ·������빦�ܣ�����SLE�������ƵĹ�ϵ�������Ƽ���SLE�����е��о���չ��

As an important intracellular signal transduction pathway, PI3K/AKT signaling pathway modulates fundamental cellular functions, including cell survival, growth, proliferation and metabolism by affecting the activation of multiple downstream effector molecules. Recent studies have found that the abnormal activation of PI3K/AKT signaling pathway in T and B lymphocytes is closely associated with the initiation and progression of autoimmunity in SLE. This article brings a review on the composition and functions of PI3K/AKT signaling pathway and its relationship with the pathogenesis of SLE, as well as on inhibitors of this pathway in the treatment of SLE.

������Ȼ��ѧ����

[1] Zhu J, Liu X, Xie C, et al. T cell hyperactivity in lupus as a consequence of hyperstimulatory antigen-presenting cells. J Clin Invest, 2005, 115(7):1869-1878. [2] Lipsky, P.E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol, 2001, 2(9):764–766. [3] Nijnik A, Ferry H, Lewis G, et al. Spontaneous B cell hyperactivity in autoimmune-prone MRL mice. Int Immunol, 2006, 18 (7):1127–1137. [4] Bozulic L, Hemmings BA. PIKKing on PKB: regulation of PKB activity by phosphorylation. Curr Opin Cell Biol, 2009, 21(2):256-261. [5] Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell, 2007, 129(7):1261-1274. [6] Franke TF. PI3K/Akt: getting it right matters. Oncogene, 2008,27(50): 6473-6488. [7] Dijkers PF, Birkenkamp KU, Lam EW, et al. FKHRL1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase Benhanced cell survival through maintenance of mitochondrial integrity. J Cell Biol, 2002, 156(3):531–542. [8] Villunger A, Michalak EM, Coultas L, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science, 2003, 302(5647):1036–1038. [9] Maurer U, Charvet C, Wagman AS, et al. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell, 2006, 21(6):749–760. [10] Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell, 2006, 124(3):471–484. [11] Vander Haar E, Lee SI, Bandhakavi S, et al. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol, 2007, 9(3):316–323. [12] Skeen JE, Bhaskar PT, Chen CC, et al. Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner. Cancer Cell, 2006, 10(4):269–280. [13] Mamane Y, Petroulakis E, Rong L, et al. eIF4E–from translation to transformation. Oncogene, 2004, 23(18):3172–3179. [14] Peng SL. Altered T and B lymphocyte signaling pathways in lupus. Autoimmun Rev, 2009, 8(3):179-83. [15] Di Cristofano A, Kotsi P, Peng YF, et al. Impaired Fas response and autoimmunity in Pten+/- mice. Science, 1999, 285(5436): 2122-2125. [16] Borlado LR, Redondo C, Alvarez B, et al. Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. FASEB J, 2000, 14(7): 895-903. [17] Barber DF, Bartolomé A, Hernandez C, et al. PI3Kgamma inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat Med, 2005, 11(9): 933-935. [18] Wu, T, Qin, X, Kurepa, Z, et al. Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. J. Clin. Invest, 2007, 117(8): 2186- 2196. [19] Tang H, Tan G, Guo Q, et al. Abnormal activation of the Akt-GSK3beta signaling pathway in peripheral blood T cells from patients with systemic lupus erythematosus. Cell Cycle, 2009, 8(17):2789-2793. [20] Fernandez DR, Telarico T, Bonilla E, Li Q, et al. Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J Immunol, 2009, 182(4):2063-2073. [21] Barber DF, Bartolomé A, Hernandez C, et al. Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion. J Immunol, 2006, 176(1):589-593. [22] Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed, 2007, 82(4):381-388. [23] Kr?mer S, Wang-Rosenke Y, Scholl V, Binder E, et al. Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat, 2008, 294(2):F440-449. [24] Tsagalis G, Psimenou E, Iliadis A, et al. Rapamycin for focal segmental glomerulosclerosis: a report of 3 cases. Am J Kidney Dis, 2009, 54(2):340-344. [25] Lui SL, Tsang R, Chan KW, et al. Rapamycin attenuates the severity of established nephritis in lupus-prone NZB/W F1 mice. Nephrol Dial Transplant, 2008, 23(9):2768-2776. [26] Ramos-Barron A, Pinera-Haces C, Gomez-Alamillo C, et al. Prevention of murine lupus disease in (NZBxNZW)F1 mice by sirolimus treatment. Lupus, 2007, 16(10):775-781. [27] Alperovich G, Rama I, Lloberas N, et al. New immunosuppresor strategies in the treatment of murine lupus nephritis. Lupus, 2007, 16(1):18-24. [28] Reddy PS, Legault HM, Sypek JP, et al. Mapping similarities in mTOR pathway perturbations in mouse lupus nephritis models and human lupus nephritis. Arthritis Res Ther, 2008, 10(6):R127. [29] Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med, 2008, 205(3):565–574. [30] Sauer S, Bruno L, Hertweck A, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA, 2008, 105(22):7797–7802. [31] Fernandez D, Bonilla E, Mirza N, et al. Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum, 2006, 54(9):2983-2988. [32] Nambiar MP, Fisher CU, Warke VG, et al. Reconstitution of deficient T cell receptor zeta chain restores T cell signaling and augments T cell receptor/CD3-induced interleukin-2 production in patients with systemic lupus erythematosus. Arthritis Rheum, 2003, 48(7):1948-1955.