Nitric oxide and thiol redox regulation of Janus kinase activity

Nitric oxide and thiol redox regulation of Janus kinase activity

^*Intramural Research Support Program, Science Applications International Corporation—Frederick, Frederick, MD 21702-1201; ^‡Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799; and ^§Cytokine Molecular Mechanisms Section, Laboratory of Molecular Immunoregulation, National Cancer Institute—Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD 21702-1201

Edited by Leonard A. Herzenberg, Stanford University School of Medicine, Stanford, CA, and approved November 3, 1997 (received for review April 16, 1997)

Abstract

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.

Footnotes

↵ † To whom reprint requests should be addressed. e-mail: DUHE{at}ncifcrf.gov.
This paper was submitted directly (Track II) to the Proceedings Office.
Abbreviations: JAK, Janus kinase; IL, interleukin; IL-2Rβ, interleukin 2 receptor β chain; DEA-NO, diethylamine/nitric oxide [sodium-l-(N,N-diethylamino)diazene-1,2-diolate].