Mechanism of Interferon-γ-Induced Increase in T84 Intestinal Epithelial Tight Junction

被引:56
作者
Boivin, Michel A. [1 ]
Roy, Praveen K. [1 ,2 ]
Bradley, Angela [1 ]
Kennedy, John C. [1 ]
Rihani, Tuhama [1 ]
Ma, Thomas Y. [1 ,2 ]
机构
[1] Univ New Mexico, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol, Albuquerque, NM 87131 USA
[2] Albuquerque Vet Affairs Med Ctr, Dept Med, Div Gastroenterol, Albuquerque, NM USA
关键词
INFLAMMATORY-BOWEL-DISEASE; NECROSIS-FACTOR-ALPHA; IFN-GAMMA; BARRIER FUNCTION; PHOSPHATIDYLINOSITOL; 3-KINASE; ULCERATIVE-COLITIS; CELLS; PERMEABILITY; MODULATION; DISRUPTION;
D O I
10.1089/jir.2008.0128
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Interferon-gamma (IFN-gamma) is an important proinflammatory cytokine that plays a central role in the intestinal inflammatory process of inflammatory bowel disease. IFN-gamma induced disturbance of the intestinal epithelial tight junction (TJ) barrier has been postulated to be an important mechanism contributing to intestinal inflammation. The intracellular mechanisms that mediate the IFN-gamma induced increase in intestinal TJ permeability remain unclear. The aim of this study was to examine the role of the phosphatidylinositol 3-kinase (PI3-K) pathway in the regulation of the IFN-gamma induced increase in intestinal TJ permeability using the T84 intestinal epithelial cell line. IFN-gamma caused an increase in T84 intestinal epithelial TJ permeability and depletion of TJ protein, occludin. The IFN-gamma induced increase in TJ permeability and alteration in occludin protein was associated with rapid activation of PI3-K; and inhibition of PI3-K activation prevented the IFN-gamma induced effects. IFN-gamma also caused a delayed but more prolonged activation of nuclear factor-kappa B (NF-kappa B); inhibition of NF-kappa B also prevented the increase in T84 TJ permeability and alteration in occludin expression. The IFN-gamma induced activation of NF-kappa B was mediated by a cross-talk with PI3-K pathway. In conclusion, the IFN-gamma induced increase in T84 TJ permeability and alteration in occludin protein expression were mediated by the PI3-K pathway. These results show for the first time that the IFN-gamma modulation of TJ protein and TJ barrier function is regulated by a cross-talk between PI3-K and NF-kappa B pathways.
引用
收藏
页码:45 / 54
页数:10
相关论文
共 29 条
[1]  
ADAMS RB, 1993, J IMMUNOL, V150, P2356
[2]   IL-1β causes an increase in intestinal epithelial tight junction permeability [J].
Al-Sadi, Rana M. ;
Ma, Thomas Y. .
JOURNAL OF IMMUNOLOGY, 2007, 178 (07) :4641-4649
[3]   Mechanism of glucocorticoid regulation of the intestinal tight junction barrier [J].
Boivin, Michel A. ;
Ye, Dongmei ;
Kennedy, John C. ;
Al-Sadi, Rana ;
Shepela, Chris ;
Ma, Thomas Y. .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2007, 292 (02) :G590-G598
[4]  
BREESE E, 1993, IMMUNOLOGY, V78, P127
[5]   Proinflammatory cytokines disrupt epithelial barrier function by apoptosis-independent mechanisms [J].
Bruewer, M ;
Luegering, A ;
Kucharzik, T ;
Parkos, CA ;
Madara, JL ;
Hopkins, AM ;
Nusrat, A .
JOURNAL OF IMMUNOLOGY, 2003, 171 (11) :6164-6172
[6]   Interferon-γ induces internalization of epithelial tight junction proteins via a macropinocytosis-like process [J].
Bruewer, M ;
Utech, M ;
Ivanov, AI ;
Hopkins, AM ;
Parkos, CA ;
Nusrat, A .
FASEB JOURNAL, 2005, 19 (08) :923-933
[7]   Interleukins 4 and 13 increase intestinal epithelial permeability by a phosphatidylinositol 3-kinase pathway - Lack of evidence for STAT 6 involvement [J].
Ceponis, PJM ;
Botelho, F ;
Richards, CD ;
McKay, DM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (37) :29132-29137
[8]  
Fuss IJ, 1996, J IMMUNOL, V157, P1261
[9]   IKKβ and phosphatidylinositol 3-kinase/Akt participate in non-pathogenic gram-negative enteric bacteria-induced RelA phosphorylation and NF-κB activation in both primary and intestinal epithelial cell lines [J].
Haller, D ;
Russo, MP ;
Sartor, RB ;
Jobin, C .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (41) :38168-38178
[10]   CROHNS-DISEASE - A PERMEABILITY DISORDER OF THE TIGHT JUNCTION [J].
HOLLANDER, D .
GUT, 1988, 29 (12) :1621-1624