Tyrosine kinase 2 controls IL-1ß production at the translational level.
IL-1beta is an important proinflammatory cytokine with a major role in several inflammatory diseases. Expression of IL-1beta is tightly regulated at the level of transcription, mRNA stability, and proteolytic processing. In this study, we report that IL-1beta expression in response to LPS is also regulated at the translational level. LPS-induced IL-1beta protein levels in macrophages derived from murine bone marrow are markedly increased in the absence of tyrosine kinase 2 (Tyk2). Increased IL-1beta is found intra- and extracellularly, irrespective of the efficiency of IL-1beta processing. We show that the absence of Tyk2 results both in higher translational rates and in enhanced association of IL-1beta mRNA with polysomes. Induction and stability of IL-1beta 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-1beta 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-1beta synthesis.
Radwan
Marta
M
Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria.
Stiefvater
Rita
R
Grunert
Tom
T
Sharif
Omar
O
Miller
Ingrid
I
Marchetti-Deschmann
Martina
M
Allmaier
Günter
G
Gemeiner
Manfred
M
Knapp
Sylvia
S
Kovarik
Pavel
P
Müller
Mathias
M
Strobl
Birgit
B
D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D007370:Interferon Type I / Q000502:physiology; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014176:Protein Biosynthesis / Q000235:genetics* / Q000276:immunology*; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D053634:TYK2 Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D007370:Interferon Type I; D053583:Interleukin-1beta; D011498:Protein Precursors; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse