Increase in the Tight Junction Protein Claudin-1 in Intestinal Inflammation
- 728 Downloads
Background and Aims
Studies have shown a decrease in key tight junction (TJ) proteins such as ZO-1 and occludin in both inflammatory bowel disease (IBD) and experimental models of inflammation. Our group has also shown an increase in claudin-1 in experimental colitis.
IEC-18 cells were treated with increasing doses of tumor necrosis factor alpha (TNFα). The TJ was assessed by transepithelial resistance (TER), permeability, Western blot, PCR, and immunofluorescence. Mucosal samples from patients with ulcerative colitis (UC), Crohn’s disease (CD), and without IBD (normal) were assayed for TJ proteins occludin and claudin-1 by Western blot and a ratio of claudin-1 to occludin (C:O) was calculated.
IEC-18 cells had increased permeability, decreased TER and an increase in claudin-1 with TNFα treatment. In human specimens, there was a decrease in occludin and an increase in claudin-1 leading to a significant increase in the C:O ratio in diseased UC colon compared to non-diseased UC colon (P < 0.001) and normal colon (P < 0.01). In CD, the C:O ratio was similar in all CD tissue irrespective of disease status.
Treatment of IEC-18 cells with TNFα, a key inflammatory cytokine in IBD, led to a significant increase in claudin-1 expression. There was a significant increase in the C:O ratio in diseased colon in UC compared to the healthy appearing UC colon and normal controls. The C:O ratio was unchanged in CD despite presence or abscence of gross disease. This suggests that there may be an underlying difference in the TJ between UC and CD.
KeywordsTNFα Crohn’s disease Ulcerative colitis Claudin-1 Occludin
Presented at Digestive Disease Week, May 2009.
NIH: K08 GM081595 (Poritz).
- 6.Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123:1777–1788.Google Scholar
- 14.Resta-Lenert S, Smitham J, Barrett KE. Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a-/- mice. Am J Physiol Gastrointest Liver Physiol. 2005;289:G153–G162. doi: 10.1152/ajpgi.00395.2004.
- 16.Schmitz H, Barmeyer C, Fromm M, et al. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology. 1999;116:301–309.Google Scholar
- 18.Oshima T, Miwa H, Joh T. Changes in the expression of claudins in active ulcerative colitis. J Gastroenterol Hepatol. 2008;23:S146–S150. doi: 10.1111/j.1440-1746.2008.05405.x.
- 19.Poritz L, Sundstrom J, Harris L, Barber A, Antonetti D. Alteration of occludin expression in intestinal inflammation. J Surg Res. 2009;151:188.Google Scholar
- 24.Antonetti DA, Wolpert EB, DeMaio L, Harhaj NS, Scaduto RC, Jr. Hydrocortisone decreases retinal endothelial cell water and solute flux coincident with increased content and decreased phosphorylation of occludin. J Neurochem. 2002;80:667–677.Google Scholar
- 25.Youakim A, Ahdieh M. Interferon-gamma decreases barrier function in T84 cells by reducing ZO-1 levels and disrupting apical actin. Am J Physiol. 1999;276:G1279–G1288.Google Scholar
- 27.Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients with Crohn’s disease and their relatives. A possible etiologic factor. Ann Intern Med. 1986;105:883–885.Google Scholar
- 28.May GR, Sutherland LR, Meddings JB. Is small intestinal permeability really increased in relatives of patients with Crohn’s disease? Gastroenterology. 1993;104:1627–1632.Google Scholar
- 29.Peeters M, Geypens B, Claus D, et al. Clustering of increased small intestinal permeability in families with Crohn’s disease. Gastroenterology. 1997;113:802–807.Google Scholar
- 35.Strater J, Wellisch I, Riedl S, et al. CD95 (APO-1/Fas)-mediated apoptosis in colon epithelial cells: a possible role in ulcerative colitis. Gastroenterology. 1997;113:160–167.Google Scholar
- 37.Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke W, Kucharzik T. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology. 2001;121:1145–1157.Google Scholar
- 39.Huo Q, Kinugasa T, Wang L, et al. Claudin-1 protein is a major factor involved in the tumorigenesis of colorectal cancer. Anticancer Res. 2009;29:851–857.Google Scholar
- 40.Kinugasa T, Huo Q, Higashi D, et al. Selective up-regulation of claudin-1 and claudin-2 in colorectal cancer. Anticancer Res. 2007;27:3729–3734.Google Scholar
- 42.Weber CR, Nalle SC, Tretiakova M, Rubin DT, Turner JR. Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation. Lab Invest. 2008;88:1110–1120. doi: 10.1038/labinvest.2008.78.