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Interferon-gamma and tumor necrosis factor-alpha disrupt epithelial barrier function by altering lipid composition in membrane microdomains of tight junction.
Clin Immunol. 2008 Jan; 126(1):67-80.CI

Abstract

Tight junctions (TJs) are specialized membrane microdomains of plasma membrane and play an important role in barrier function. IFN-gamma and TNF-alpha have been implicated in intestinal barrier dysfunction. In the present study, we analyzed the effect of IFN-gamma and TNF-alpha on epithelial barrier function and determined the contribution of apoptosis to this process using T84 cells, a model intestinal epithelial cell line. We found that TNF-alpha and IFN-gamma synergistically affected the epithelial barrier and disrupted the structure of TJs. We demonstrated for the first time that treatment with TNF-alpha and IFN-gamma changed lipid composition and fatty acyl substitutions of phospholipids in membrane microdomains of TJs. Alterations of lipid environment affected TJs barrier function and partly removed flotillin-1 and displaced occludin from membrane microdomains of TJs to detergent-soluble fractions. The distribution of claudin isoforms was unaffected by TNF-alpha and IFN-gamma treatment. These findings indicated the interaction between inflammatory cytokines and alterations of lipid composition in membrane microdomains of TJs in the inflammatory processes. The apoptosis inhibitor did not prevent cytokine-induced decrease in TER and increase in permeability to FITC-dextran. Our results suggest that the cytokines directly influence TJ function and modulate both the membrane microdomain localization of TJ proteins and lipid composition of TJs. The effects of proinflammatory cytokines on TJ structure and function provide a mechanism in the pathophysiology of Crohn's disease (CD). Understanding the intracellular mechanisms involved could be important in devising future therapeutic strategies to induce retightening of the leaky TJ barrier.

Authors+Show Affiliations

Institute of General Surgery, Jinling Hospital, Nanjing, PR China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17964857

Citation

Li, Qiurong, et al. "Interferon-gamma and Tumor Necrosis Factor-alpha Disrupt Epithelial Barrier Function By Altering Lipid Composition in Membrane Microdomains of Tight Junction." Clinical Immunology (Orlando, Fla.), vol. 126, no. 1, 2008, pp. 67-80.
Li Q, Zhang Q, Wang M, et al. Interferon-gamma and tumor necrosis factor-alpha disrupt epithelial barrier function by altering lipid composition in membrane microdomains of tight junction. Clin Immunol. 2008;126(1):67-80.
Li, Q., Zhang, Q., Wang, M., Zhao, S., Ma, J., Luo, N., Li, N., Li, Y., Xu, G., & Li, J. (2008). Interferon-gamma and tumor necrosis factor-alpha disrupt epithelial barrier function by altering lipid composition in membrane microdomains of tight junction. Clinical Immunology (Orlando, Fla.), 126(1), 67-80.
Li Q, et al. Interferon-gamma and Tumor Necrosis Factor-alpha Disrupt Epithelial Barrier Function By Altering Lipid Composition in Membrane Microdomains of Tight Junction. Clin Immunol. 2008;126(1):67-80. PubMed PMID: 17964857.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Interferon-gamma and tumor necrosis factor-alpha disrupt epithelial barrier function by altering lipid composition in membrane microdomains of tight junction. AU - Li,Qiurong, AU - Zhang,Qiang, AU - Wang,Meng, AU - Zhao,Sumin, AU - Ma,Jian, AU - Luo,Nan, AU - Li,Ning, AU - Li,Yousheng, AU - Xu,Guowang, AU - Li,Jieshou, Y1 - 2007/10/26/ PY - 2006/07/27/received PY - 2007/08/14/revised PY - 2007/08/20/accepted PY - 2007/10/30/pubmed PY - 2008/2/26/medline PY - 2007/10/30/entrez SP - 67 EP - 80 JF - Clinical immunology (Orlando, Fla.) JO - Clin Immunol VL - 126 IS - 1 N2 - Tight junctions (TJs) are specialized membrane microdomains of plasma membrane and play an important role in barrier function. IFN-gamma and TNF-alpha have been implicated in intestinal barrier dysfunction. In the present study, we analyzed the effect of IFN-gamma and TNF-alpha on epithelial barrier function and determined the contribution of apoptosis to this process using T84 cells, a model intestinal epithelial cell line. We found that TNF-alpha and IFN-gamma synergistically affected the epithelial barrier and disrupted the structure of TJs. We demonstrated for the first time that treatment with TNF-alpha and IFN-gamma changed lipid composition and fatty acyl substitutions of phospholipids in membrane microdomains of TJs. Alterations of lipid environment affected TJs barrier function and partly removed flotillin-1 and displaced occludin from membrane microdomains of TJs to detergent-soluble fractions. The distribution of claudin isoforms was unaffected by TNF-alpha and IFN-gamma treatment. These findings indicated the interaction between inflammatory cytokines and alterations of lipid composition in membrane microdomains of TJs in the inflammatory processes. The apoptosis inhibitor did not prevent cytokine-induced decrease in TER and increase in permeability to FITC-dextran. Our results suggest that the cytokines directly influence TJ function and modulate both the membrane microdomain localization of TJ proteins and lipid composition of TJs. The effects of proinflammatory cytokines on TJ structure and function provide a mechanism in the pathophysiology of Crohn's disease (CD). Understanding the intracellular mechanisms involved could be important in devising future therapeutic strategies to induce retightening of the leaky TJ barrier. SN - 1521-6616 UR - https://www.unboundmedicine.com/medline/citation/17964857/Interferon_gamma_and_tumor_necrosis_factor_alpha_disrupt_epithelial_barrier_function_by_altering_lipid_composition_in_membrane_microdomains_of_tight_junction_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1521-6616(07)01330-7 DB - PRIME DP - Unbound Medicine ER -