A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1

Nat Immunol. 2009 May;10(5):471-9. doi: 10.1038/ni.1722. Epub 2009 Apr 6.

Abstract

A common mutation in the gene encoding the cytoplasmic sensor Nod2, involving a frameshift insertion at nucleotide 3020 (3020insC), is strongly associated with Crohn's disease. How 3020insC contributes to this disease is a controversial issue. Clinical studies have identified defective production of interleukin 10 (IL-10) in patients with Crohn's disease who bear the 3020insC mutation, which suggests that 3020insC may be a loss-of-function mutation. However, here we found that 3020insC Nod2 mutant protein actively inhibited IL10 transcription. The 3020insC Nod2 mutant suppressed IL10 transcription by blocking phosphorylation of the nuclear ribonucleoprotein hnRNP-A1 via the mitogen-activated protein kinase p38. We confirmed impairment in phosphorylation of hnRNP-A1 and binding of hnRNP-A1 to the IL10 locus in peripheral blood mononuclear cells from patients with Crohn's disease who bear the 3020insC mutation and have lower production of IL-10.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Crohn Disease / genetics*
  • Crohn Disease / immunology
  • Crohn Disease / metabolism
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism*
  • Humans
  • Interleukin-10 / biosynthesis*
  • Interleukin-10 / genetics
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Monocytes / immunology
  • Monocytes / metabolism
  • Mutation
  • Nod2 Signaling Adaptor Protein / genetics*
  • Transcription, Genetic

Substances

  • Heterogeneous Nuclear Ribonucleoprotein A1
  • Heterogeneous-Nuclear Ribonucleoprotein Group A-B
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • Interleukin-10