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


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.
Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. michael.scharl@usz.ch
Michael
M
Scharl
Jessica
J
Mwinyi
Anne
A
Fischbeck
Katharina
K
Leucht
Jyrki J
JJ
Eloranta
Joba
J
Arikkat
Theresa
T
Pesch
Silvia
S
Kellermeier
Alma
A
Mair
Gerd A
GA
Kullak-Ublick
Kaspar
K
Truninger
Faiza
F
Noreen
Jaroslaw
J
Regula
Pawel
P
Gaj
Valerie
V
Pittet
Christoph
C
Mueller
Claudia
C
Hofmann
Michael
M
Fried
Declan F
DF
McCole
Gerhard
G
Rogler
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000328:Adult; D001343:Autophagy; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D015331:Cohort Studies; D003106:Colon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003424:Crohn Disease / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism*; D004247:DNA / Q000097:blood / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D000098815:T-bet Transcription Factor
D000276:Adjuvants, Immunologic; D014408:Biomarkers, Tumor; D016207:Cytokines; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D007371:Interferon-gamma; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; C516649:PTPN2 protein, human; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2