Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease

J Exp Med. 2013 Aug 26;210(9):1675-84. doi: 10.1084/jem.20120707. Epub 2013 Aug 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • AU Rich Elements / genetics
  • Animals
  • Bone Diseases, Metabolic / diagnostic imaging
  • Bone Diseases, Metabolic / genetics
  • Bone Diseases, Metabolic / pathology
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Bone Remodeling / drug effects
  • Bone Remodeling / genetics
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Dendritic Cells / pathology
  • HEK293 Cells
  • Humans
  • Inflammation / genetics*
  • Inflammation / prevention & control*
  • Interleukin-17 / metabolism
  • Interleukin-22
  • Interleukin-23 / biosynthesis
  • Interleukin-23 / genetics*
  • Interleukin-23 Subunit p19 / metabolism
  • Interleukins / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • RNA Stability / drug effects
  • RNA Stability / genetics*
  • Radiography
  • Syndrome
  • Tristetraprolin / deficiency
  • Tristetraprolin / metabolism*

Substances

  • 3' Untranslated Regions
  • Il23a protein, mouse
  • Interleukin-17
  • Interleukin-23
  • Interleukin-23 Subunit p19
  • Interleukins
  • Lipopolysaccharides
  • Tristetraprolin