Frantz B, Nordby E C, Bren G, Steffan N, Paya C V, Kincaid R L, Tocci M J, O'Keefe S J, O'Neill E A
Department of Molecular Immunology, Merck Research Laboratories, Rahway, NJ 07065.
EMBO J. 1994 Feb 15;13(4):861-70. doi: 10.1002/j.1460-2075.1994.tb06329.x.
The interleukin-2 (IL-2) promoter consists of several independent T cell receptor (TcR) responsive elements. The induction of promoters dependent on these elements is inhibitable by the immunosuppressants cyclosporin A (CsA) and tacrolimus (FK-506). Calcineurin, a Ca2+/calmodulin-dependent protein phosphatase, is the FK-506- and CsA-sensitive enzyme required for TcR mediated activation of the IL-2 promoter. We report that a constitutively active form of calcineurin partially substitutes for the Ca2+ co-stimulus required to activate the IL-2 promoter elements IL-2A (which binds the factors OAP and Oct-1) and IL-2E (which binds NF-AT), and completely substitutes for the Ca2+ co-stimulus required to stimulate an NF-kappa B-dependent element. Calcineurin stimulates the NF-kappa B element by enhancing inactivation of I kappa B/MAD3, an inhibitor of NF-kappa B, thereby increasing the amount of nuclear NF-kappa B DNA binding activity. These data provide the first demonstration in vivo that activation of a protein phosphatase can inactivate I kappa B, and suggest one possible explanation for mechanism-based toxicities associated with FK-506 and CsA by demonstrating that these drugs can inhibit the calcineurin-dependent activation of a virtually ubiquitous transcription factor.
白细胞介素-2（IL-2）启动子由几个独立的T细胞受体（TcR）反应元件组成。依赖于这些元件的启动子的诱导可被免疫抑制剂环孢菌素A（CsA）和他克莫司（FK-506）抑制。钙调神经磷酸酶是一种Ca2+/钙调蛋白依赖性蛋白磷酸酶，是TcR介导的IL-2启动子激活所需的对FK-506和CsA敏感的酶。我们报告，一种组成型活性形式的钙调神经磷酸酶部分替代了激活IL-2启动子元件IL-2A（结合因子OAP和Oct-1）和IL-2E（结合NF-AT）所需的Ca2+共刺激，并完全替代了刺激NF-κB依赖性元件所需的Ca2+共刺激。钙调神经磷酸酶通过增强NF-κB抑制剂IκB/MAD3的失活来刺激NF-κB元件，从而增加核NF-κB DNA结合活性的量。这些数据首次在体内证明了蛋白磷酸酶的激活可以使IκB失活，并通过证明这些药物可以抑制一种几乎普遍存在的转录因子的钙调神经磷酸酶依赖性激活，为与FK-506和CsA相关的基于机制的毒性提供了一种可能的解释。
