Crohn's disease-associated polymorphism within the PTPN2 gene affects muramyl-dipeptide-induced cytokine secretion and autophagy

Inflamm Bowel Dis. 2012 May;18(5):900-12. doi: 10.1002/ibd.21913. Epub 2011 Oct 21.


Background: The single nucleotide polymorphism (SNP) rs2542151 within the gene locus region encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) has been associated with Crohn's disease (CD), ulcerative colitis (UC), type-I diabetes, and rheumatoid arthritis. We have previously shown that PTPN2 regulates mitogen-activated protein kinase (MAPK) signaling and cytokine secretion in human THP-1 monocytes and intestinal epithelial cells (IEC). Here, we studied whether intronic PTPN2 SNP rs1893217 regulates immune responses to the nucleotide-oligomerization domain 2 (NOD2) ligand, muramyl-dipeptide (MDP).

Materials and methods: Genomic DNA samples from 343 CD and 663 non-IBD control patients (male and female) from a combined German, Swiss, and Polish cohort were genotyped for the presence of the PTPN2 SNPs, rs2542151, and rs1893217. PTPN2-variant rs1893217 was introduced into T(84) IEC or THP-1 cells using a lentiviral vector.

Results: We identified a novel association between the genetic variant, rs1893217, located in intron 7 of the PTPN2 gene and CD. Human THP-1 monocytes carrying this variant revealed increased MAPK activation as well as elevated mRNA expression of T-bet transcription factor and secretion of interferon-γ in response to the bacterial wall component, MDP. In contrast, secretion of interleukin-8 and tumor necrosis factor were reduced. In both, T(84) IEC and THP-1 monocytes, autophagosome formation was impaired.

Conclusions: We identified a novel CD-associated PTPN2 variant that modulates innate immune responses to bacterial antigens. These findings not only provide key insights into the effects of a functional mutation on a clinically relevant gene, but also reveal how such a mutation could contribute to the onset of disease.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylmuramyl-Alanyl-Isoglutamine / pharmacology*
  • Adjuvants, Immunologic / pharmacology*
  • Adult
  • Autophagy*
  • Biomarkers, Tumor / genetics*
  • Blotting, Western
  • Case-Control Studies
  • Cells, Cultured
  • Cohort Studies
  • Colon / cytology
  • Colon / drug effects
  • Colon / metabolism
  • Crohn Disease / genetics*
  • Crohn Disease / immunology
  • Cytokines / metabolism*
  • DNA / blood
  • DNA / genetics
  • Female
  • Fluorescent Antibody Technique
  • Genotype
  • Haplotypes / genetics
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Interferon-gamma / metabolism
  • Male
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Monocytes / cytology
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / metabolism
  • Phosphorylation / drug effects
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism


  • Adjuvants, Immunologic
  • Biomarkers, Tumor
  • Cytokines
  • Nod2 Signaling Adaptor Protein
  • RNA, Messenger
  • RNA, Small Interfering
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Acetylmuramyl-Alanyl-Isoglutamine
  • Interferon-gamma
  • DNA
  • Mitogen-Activated Protein Kinases
  • PTPN2 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2