TY - JOUR
T1 - Larazotide acetate regulates epithelial tight junctions in vitro and in vivo
AU - Gopalakrishnan, Shobha
AU - Durai, Malarvizhi
AU - Kitchens, Kelly
AU - Tamiz, Amir P.
AU - Somerville, Robert
AU - Ginski, Mark
AU - Paterson, Blake M.
AU - Murray, Joseph A.
AU - Verdu, Elena F.
AU - Alkan, Sefik S.
AU - Pandey, Niranjan B.
N1 - Funding Information:
This work was partially supported by grants from the Canadian Association of Gastroenterology (CAG) / Canadian Institute of Health Research (CIHR) ( GN2-114709 ), the Canadian Celiac Association New Investigator Award (to E. Verdu), and ALBA Therapeutics. E. Verdu holds a McMaster University Dep. of Medicine Internal Career Research Award. Joseph Murray was supported by NIH grant DK 70031 . We are grateful to Drs. Alessio Fasano, Linda Arterburn, and Francisco Leon for critical reading of the manuscript.
PY - 2012/5
Y1 - 2012/5
N2 - Tight junctions (TJs) control paracellular permeability and apical-basolateral polarity of epithelial cells, and can be regulated by exogenous and endogenous stimuli. Dysregulated permeability is associated with pathological conditions, such as celiac disease and inflammatory bowel disease. Herein we studied the mechanism by which larazotide acetate, an 8-mer peptide and TJ regulator, inhibits the cellular changes elicited by gliadin fragments, AT-1002, and cytokines. Previously, we demonstrated that AT-1002, a 6-mer peptide derived from the Vibrio cholerae zonula occludens toxin ZOT, caused several biochemical changes in IEC6 and Caco-2 cells resulting in decreased transepithelial electrical resistance (TEER) and increased TJ permeability. In this study, larazotide acetate inhibited the redistribution and rearrangement of zonula occludens-1 (ZO-1) and actin caused by AT-1002 and gliadin fragments in Caco-2 and IEC6 cells. Functionally, larazotide acetate inhibited the AT-1002-induced TEER reduction and TJ opening in Caco-2 cells. Additionally, larazotide acetate inhibited the translocation of a gliadin 13-mer peptide, which has been implicated in celiac disease, across Caco-2 cell monolayers. Further, apically applied larazotide acetate inhibited the increase in TJ permeability elicited by basolaterally applied cytokines. Finally, when tested in vivo in gliadin-sensitized HLA-HCD4/DQ8 double transgenic mice, larazotide acetate inhibited gliadin-induced macrophage accumulation in the intestine and preserved normal TJ structure. Taken together, our data suggest that larazotide acetate inhibits changes elicited by AT-1002, gliadin, and cytokines in epithelial cells and preserves TJ structure and function in vitro and in vivo.
AB - Tight junctions (TJs) control paracellular permeability and apical-basolateral polarity of epithelial cells, and can be regulated by exogenous and endogenous stimuli. Dysregulated permeability is associated with pathological conditions, such as celiac disease and inflammatory bowel disease. Herein we studied the mechanism by which larazotide acetate, an 8-mer peptide and TJ regulator, inhibits the cellular changes elicited by gliadin fragments, AT-1002, and cytokines. Previously, we demonstrated that AT-1002, a 6-mer peptide derived from the Vibrio cholerae zonula occludens toxin ZOT, caused several biochemical changes in IEC6 and Caco-2 cells resulting in decreased transepithelial electrical resistance (TEER) and increased TJ permeability. In this study, larazotide acetate inhibited the redistribution and rearrangement of zonula occludens-1 (ZO-1) and actin caused by AT-1002 and gliadin fragments in Caco-2 and IEC6 cells. Functionally, larazotide acetate inhibited the AT-1002-induced TEER reduction and TJ opening in Caco-2 cells. Additionally, larazotide acetate inhibited the translocation of a gliadin 13-mer peptide, which has been implicated in celiac disease, across Caco-2 cell monolayers. Further, apically applied larazotide acetate inhibited the increase in TJ permeability elicited by basolaterally applied cytokines. Finally, when tested in vivo in gliadin-sensitized HLA-HCD4/DQ8 double transgenic mice, larazotide acetate inhibited gliadin-induced macrophage accumulation in the intestine and preserved normal TJ structure. Taken together, our data suggest that larazotide acetate inhibits changes elicited by AT-1002, gliadin, and cytokines in epithelial cells and preserves TJ structure and function in vitro and in vivo.
KW - Actin
KW - Celiac disease
KW - Gliadin
KW - Permeability inducer
KW - Tight junction
KW - ZO-1
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U2 - 10.1016/j.peptides.2012.02.015
DO - 10.1016/j.peptides.2012.02.015
M3 - Article
C2 - 22401908
AN - SCOPUS:84859805588
SN - 0196-9781
VL - 35
SP - 86
EP - 94
JO - Peptides
JF - Peptides
IS - 1
ER -