Duhé R J, Evans G A, Erwin R A, Kirken R A, Cox G W, Farrar W L
Intramural Research Support Program, Science Applications International Corporation-Frederick, Frederick, MD 21702-1201, USA.
Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):126-31. doi: 10.1073/pnas.95.1.126.
The activation of Janus kinases (JAKs) is crucial for propagation of the proliferative response initiated by many cytokines. The proliferation of various cell lines, particularly those of hematopoietic origin, is also modulated by mediators of oxidative stress such as nitric oxide and thiol redox reagents. Herein we demonstrate that nitric oxide and other thiol oxidants can inhibit the autokinase activity of rat JAK2 in vitro, presumably through oxidation of crucial dithiols to disulfides within JAK2. The reduced form of JAK2 is the most active form, and the oxidized JAK2 form is inactive. Nitric oxide pretreatment of quiescent Ba/F3 cells also inhibits the interleukin 3-triggered in vivo activation of JAK2, a phenomenon that correlates with inhibited proliferation. Furthermore, we observed that the autokinase activity of JAK3 responds in a similar fashion to thiol redox reagents in vitro and to nitric oxide donors in vivo. We suggest that the thiol redox regulation of JAKs may partially explain the generally immunosuppressive effects of nitric oxide and of other thiol oxidants.
Janus激酶（JAKs）的激活对于许多细胞因子引发的增殖反应的传播至关重要。各种细胞系的增殖，尤其是造血来源的细胞系，也受到氧化应激介质如一氧化氮和硫醇氧化还原试剂的调节。在此我们证明，一氧化氮和其他硫醇氧化剂在体外可抑制大鼠JAK2的自身激酶活性，推测是通过将JAK2内关键的二硫醇氧化为二硫化物。JAK2的还原形式是最具活性的形式，而氧化形式的JAK2则无活性。对静止的Ba/F3细胞进行一氧化氮预处理也会抑制白细胞介素3触发的JAK2在体内的激活，这一现象与增殖受抑制相关。此外，我们观察到JAK3的自身激酶活性在体外对硫醇氧化还原试剂以及在体内对一氧化氮供体的反应方式类似。我们认为，JAKs的硫醇氧化还原调节可能部分解释了一氧化氮和其他硫醇氧化剂普遍的免疫抑制作用。
