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

Nature Immunology volume 10, pages 471–479 (2009)Cite this article

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.

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Figure 1: Influence of Nod2 signaling on macrophage cytokine production.
Figure 2: Different effects of wild-type and 3020insC Nod2 on endogenous IL-10 expression in primary human monocytes.
Figure 3: Inhibition of IL10 transcription by 3020insC Nod2.
Figure 4: Human and mouse Nod2 mutant proteins have different transcriptional effects.
Figure 5: Binding of nuclear proteins to the NRE.
Figure 6: Stimulation of IL10 transcription by hnRNP-A1.
Figure 7: Binding of hnRNP-A1 to the IL10 NRE.
Figure 8: Nod2–hnRNP-A1 interaction and phosphorylation of hnRNP-A1 by p38.

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Acknowledgements

We thank P.J. Murray (St. Jude Children's Research Hospital) for Nod2-knockout and control littermate mice; E. Pamer (Memorial Sloan-Kettering Cancer Center) for RICK-knockout (RIP2-knockout) and control mice; J.M. Park (Harvard University School of Medicine) for mice with conditional knockout of p38α; and G. Nunez (University of Michigan) for the mouse Nod2 expression vector and mouse 2939insC Nod2. Supported by the Broad Medical Research Program (IBD-210R2 to X.M.).

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Authors and Affiliations

  1. Department of Surgery II, Tokyo Women's Medical University, Tokyo, Japan

    Eiichiro Noguchi & Yoichiro Homma

  2. Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, USA

    Xiaoyan Kang & Xiaojing Ma

  3. Department of Medicine (463), Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    Mihai G Netea

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  1. Eiichiro Noguchi
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Contributions

E.N. contributed to the work in Figures 3,4,6,8; Y.H. contributed to the work in Figures 1, 2, 3, 4, 5, 6, 7; X.K. contributed to Figure 4; M.G.N. contributed to Figures 1,7,8; and X.M. contributed to the overall project.

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Correspondence to Xiaojing Ma.

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Supplementary Figures 1–3, Supplementary Table 1 and Supplementary Methods (PDF 708 kb)

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Noguchi, E., Homma, Y., Kang, X. et al. A Crohn's disease–associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nat Immunol 10, 471–479 (2009). https://doi.org/10.1038/ni.1722

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