Tyrosine Kinase 2 Controls IL-1β Production at the Translational Level

IL-1 beta is an important proinflammatory cytokine with a major role in several inflammatory diseases. Expression of IL-1 beta is tightly regulated at the level of transcription, mRNA stability, and proteolytic processing. In this study, we report that IL-1 beta expression in response to LPS is also regulated at the translational level. LPS-induced IL-1 beta protein levels in macrophages derived from murine bone marrow are markedly increased in the absence of tyrosine kinase 2 (Tyk2). Increased IL-1 beta is found intra- and extracellularly, irrespective of the efficiency of IL-1 beta processing. We show that the absence of Tyk2 results both in higher translational rates and in enhanced association of IL-1 beta mRNA with polysomes. Induction and stability of IL-1 beta mRNA are not affected by the lack of Tyk2. We show further that the Tyk2-dependent translational inhibition is mediated by autocrine/paracrine type I IFN signaling and requires signal transducer and activator of transcription 1. Enhanced IL-1 beta production in Tyk2- and IFN receptor 1-deficient macrophages is also observed following Listeria monocytogenes infection. Taken together, the data describe a novel mechanism for the control of IL-1 beta synthesis. The Journal of Immunology, 2010, 185: 3544-3553.