Abstract
Background/Aims: Genetic polymorphisms within the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) have been associated with inflammatory bowel disease (IBD). A recent study demonstrated that PTPN2 regulates ER stress signalling in pancreatic β-cells. Therefore, we investigated whether PTPN2 regulates ER stress pathways, apoptosis and cytokine secretion in human intestinal epithelial cells (IECs) and monocytes. Methods: THP-1 and HT-29 IECs were stimulated with 2 µg/ml tunicamycin (TNM) for the indicated periods of time. For knockdown experiments, cells were transfected using a mixture of three different PTPN2-specific siRNA oligonucleotides. Cell lysates were analysed by Western blot and real-time PCR. Cytokine secretion was studied by ELISA measurements of cell culture supernatant. Results: TNM treatment reduced PTPN2 protein levels in HT-29 IECs and THP-1 monocytes. Knockdown of PTPN2 in THP-1 monocytes led to an exaggerated induction of phospho-eIF2α, enhanced PARP cleavage, indicative of apoptosis, and attenuated IL-8 and TNF secretion upon TNM stimulation. In HT-29 cells PTPN2 deficiency caused reduced phosphorylation of eIF2α and PARP cleavage under ER stress conditions. Conclusions: Whereas the knockdown of PTPN2 made THP-1 cells more susceptible to ER stress, PTPN2 deficiency reduced ER stress responses in HT-29 IECs. This suggests that PTPN2 regulates adaptation to ER stress in a cell type-specific manner.
Journal Section:
Original Paper
References
1.
Barreiro-de Acosta M, Alvarez Castro A, Souto R, Iglesias M, Lorenzo A, Dominguez-Munoz JE: Emigration to western industrialized countries: a risk factor for developing inflammatory bowel disease. J Crohns Colitis 2011;5:566-569.
[PubMed]
2.
Podolsky DK: Inflammatory bowel disease. N Engl J Med 2002;347:417-429.
[PubMed]
3.
Fiocchi C: Inflammatory bowel disease pathogenesis: therapeutic implications. Chin J Dig Dis 2005;6:6-9.
[PubMed]
4.
Lees CW, Barrett JC, Parkes M, Satsangi J: New IBD genetics: common pathways with other diseases. Gut 2011;60:1739-1753.
[PubMed]
5.
Wellcome Trust Case Control Consortium: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447:661-678.
[PubMed]
6.
Franke A, Balschun T, Karlsen TH, Hedderich J, May S, Lu T, Schuldt D, Nikolaus S, Rosenstiel P, Krawczak M, Schreiber S: Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat Genet 2008;40:713-715.
[PubMed]
7.
Okada Y, Terao C, Ikari K, Kochi Y, Ohmura K, Suzuki A, Kawaguchi T, Stahl EA, Kurreeman FA, Nishida N, Ohmiya H, Myouzen K, Takahashi M, Sawada T, Nishioka Y, Yukioka M, Matsubara T, Wakitani S, Teshima R, Tohma S, Takasugi K, Shimada K, Murasawa A, Honjo S, Matsuo K, Tanaka H, Tajima K, Suzuki T, Iwamoto T, Kawamura Y, Tanii H, Okazaki Y, Sasaki T, Gregersen PK, Padyukov L, Worthington J, Siminovitch KA, Lathrop M, Taniguchi A, Takahashi A, Tokunaga K, Kubo M, Nakamura Y, Kamatani N, Mimori T, Plenge RM, Yamanaka H, Momohara S, Yamada R, Matsuda F, Yamamoto K: Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nat Genet 2012;44:511-516.
[PubMed]
8.
Cobb JE, Plant D, Flynn E, Tadjeddine M, Dieude P, Cornelis F, Arlestig L, Dahlqvist SR, Goulielmos G, Boumpas DT, Sidiropoulos P, Krintel SB, Ornbjerg LM, Hetland ML, Klareskog L, Haeupl T, Filer A, Buckley CD, Raza K, Witte T, Schmidt RE, FitzGerald O, Veale D, Eyre S, Worthington J: Identification of the tyrosine-protein phosphatase non-receptor type 2 as a rheumatoid arthritis susceptibility locus in Europeans. PLoS One 2013;8:e66456.
[PubMed]
9.
Garg AD, Kaczmarek A, Krysko O, Vandenabeele P, Krysko DV, Agostinis P: ER stress-induced inflammation: does it aid or impede disease progression? Trends Mol Med 2012;18:589-598.
[PubMed]
10.
Dufey E, Sepulveda D, Rojas-Rivera D, Hetz C: Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview. Am J Physiol Cell Physiol 2014;307:C582-C594.
[PubMed]
11.
Kim I, Xu W, Reed JC: Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 2008;7:1013-1030.
[PubMed]
12.
Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH, Blumberg RS: XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008;134:743-756.
[PubMed]
13.
Di Sabatino A, Ciccocioppo R, Luinetti O, Ricevuti L, Morera R, Cifone MG, Solcia E, Corazza GR: Increased enterocyte apoptosis in inflamed areas of Crohn's disease. Dis Colon Rectum 2003;46:1498-1507.
[PubMed]
14.
Schulzke JD, Bojarski C, Zeissig S, Heller F, Gitter AH, Fromm M: Disrupted barrier function through epithelial cell apoptosis. Ann N Y Acad Sci 2006;1072:288-299.
[PubMed]
15.
Iwamoto M, Koji T, Makiyama K, Kobayashi N, Nakane PK: Apoptosis of crypt epithelial cells in ulcerative colitis. J Pathol 1996;180:152-159.
[PubMed]
16.
Gitter AH, Bendfeldt K, Schulzke JD, Fromm M: Leaks in the epithelial barrier caused by spontaneous and TNF-alpha-induced single-cell apoptosis. FASEB J 2000;14:1749-1753.
[PubMed]
17.
Abreu-Martin MT, Vidrich A, Lynch DH, Targan SR: Divergent induction of apoptosis and IL-8 secretion in HT-29 cells in response to TNF-alpha and ligation of fas antigen. J Immunol 1995;155:4147-4154.
[PubMed]
18.
Peppelenbosch MP, van Deventer SJ: T cell apoptosis and inflammatory bowel disease. Gut 2004;53:1556-1558.
[PubMed]
19.
Di Sabatino A, Corazza GR: Surviving too long in Crohn's disease. Gut 2001;49:6-8.
[PubMed]
20.
Bettaieb A, Liu S, Xi Y, Nagata N, Matsuo K, Matsuo I, Chahed S, Bakke J, Keilhack H, Tiganis T, Haj FG: Differential regulation of endoplasmic reticulum stress by protein tyrosine phosphatase 1B and T cell protein tyrosine phosphatase. J Biol Chem 2011;286:9225-9235.
[PubMed]
21.
Scharl M, Paul G, Weber A, Jung BC, Docherty MJ, Hausmann M, Rogler G, Barrett KE, McCole DF: Protection of epithelial barrier function by the Crohn's disease associated gene protein tyrosine phosphatase n2. Gastroenterology 2009;137:2030-2040.e5.
[PubMed]
22.
Scharl M, McCole DF, Weber A, Vavricka SR, Frei P, Kellermeier S, Pesch T, Fried M, Rogler G: Protein tyrosine phosphatase N2 regulates TNFalpha-induced signalling and cytokine secretion in human intestinal epithelial cells. Gut 2011;60:189-197.
[PubMed]
23.
Scharl M, Hruz P, McCole DF: Protein tyrosine phosphatase non-receptor Type 2 regulates IFn-gamma-induced cytokine signaling in THP-1 monocytes. Inflamm Bowel Dis 2010;16:2055-2064.
[PubMed]
24.
Scharl M, Vavricka SR, Rogler G: Review: new anti-cytokines for IBD: what is in the pipeline? Curr Drug Targets 2013;14:1405-1420.
[PubMed]
25.
Wang HQ, Imai Y, Kataoka A, Takahashi R: Cell type-specific upregulation of Parkin in response to ER stress. Antioxid Redox Signal 2007;9:533-542.
[PubMed]
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