Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease.
Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine-rich element (ARE)-binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow-derived dendritic cells (BMDCs) from TTP(-/-) mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3' untranslated region. TTP(-/-) mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating γδ T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23-IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation.
Institute for Medical Immunology (IMI), 2 Laboratoire de Biologie Moléculaire du Gène, and 3 Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Charleroi-Gosselies, Belgium.
Céline
C
Molle
Tong
T
Zhang
Laure
L
Ysebrant de Lendonck
Cyril
C
Gueydan
Mathieu
M
Andrianne
Félicie
F
Sherer
Gaetan
G
Van Simaeys
Perry J
PJ
Blackshear
Oberdan
O
Leo
Stanislas
S
Goriely
D020413:3' Untranslated Regions / Q000235:genetics; D063307:AU Rich Elements / Q000235:genetics; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000517:prevention & control*; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000096:biosynthesis / Q000235:genetics*; D053760:Interleukin-23 Subunit p19 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics*; D011859:Radiography; D013577:Syndrome; D051816:Tristetraprolin / Q000172:deficiency / Q000378:metabolism*; D000097043:Interleukin-22
D020413:3' Untranslated Regions; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D008070:Lipopolysaccharides; D051816:Tristetraprolin; D000097043:Interleukin-22; C508841:Il23a protein, mouse