NITRIC-OXIDE AND THIOL REDOX REGULATION OF JANUS KINASE-ACTIVITY

The activation of Janus kinases (JAKs) is crucial for propagation of t he proliferative response initiated by many cytokines. The proliferati on of various cell lines, particularly those of hematopoietic origin, is also modulated by mediators of oxidative stress such as nitric oxid e and thiol redox reagents. Herein we demonstrate that nitric oxide an d other thiol oxidants can inhibit the autokinase activity of rat JAK2 in vitro, presumably through oxidation of crucial dithiols to disulfi des within JAK2. The reduced form of JAK2 is the most active form, and the oxidized JAK2 form is inactive. Nitric oxide pretreatment of quie scent Ba/F3 cells also inhibits the interleukin 3-triggered in vivo ac tivation of JAK2, a phenomenon that correlates with inhibited prolifer ation. Furthermore, we observed that the autokinase activity of JAK3 r esponds in a similar fashion to thiol redox reagents irt vitro and to nitric oxide donors in vivo. We suggest that the thiol redox regulatio n of JAKs may partially explain the generally immunosuppressive effect s of nitric oxide and of other thiol oxidants.