Tags

Type your tag names separated by a space and hit enter

Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression.
Am J Pathol. 2017 Dec; 187(12):2698-2710.AJ

Abstract

Lipopolysaccharides (LPSs) are a major component of the Gram-negative bacterial cell wall and play an important role in mediating intestinal inflammatory responses in inflammatory bowel disease. Although recent studies suggested that physiologically relevant concentrations of LPS (0 to 1 ng/mL) cause an increase in intestinal epithelial tight junction (TJ) permeability, the mechanisms that mediate an LPS-induced increase in intestinal TJ permeability remain unclear. Herein, we show that myosin light chain kinase (MLCK) plays a central role in the LPS-induced increase in TJ permeability. Filter-grown Caco-2 intestinal epithelial monolayers and C57BL/6 mice were used as an in vitro and in vivo intestinal epithelial model system, respectively. LPS caused a dose- and time-dependent increase in MLCK expression and kinase activity in Caco-2 monolayers. The pharmacologic MLCK inhibition and siRNA-induced knock-down of MLCK inhibited the LPS-induced increase in Caco-2 TJ permeability. The LPS increase in TJ permeability was mediated by toll-like receptor 4 (TLR-4)/MyD88 signal-transduction pathway up-regulation of MLCK expression. The LPS-induced increase in mouse intestinal permeability also required an increase in MLCK expression. The LPS-induced increase in intestinal permeability was inhibited in MLCK-/- and TLR-4-/- mice. These data show, for the first time, that the LPS-induced increase in intestinal permeability was mediated by TLR-4/MyD88 signal-transduction pathway up-regulation of MLCK. Therapeutic targeting of these pathways can prevent an LPS-induced increase in intestinal permeability.

Links

PMC Free PDF

Authors+Show Affiliations

Nighot M
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico.
Al-Sadi R
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
Guo S
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
Rawat M
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico.
Nighot P
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico.
Watterson MD
Drug Discovery Program, Northwestern University, Chicago, Illinois.
Ma TY
Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico; Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico. Electronic address: tma@salud.unm.edu.

MeSH

AnimalsCaco-2 CellsHumansInflammationIntestinal MucosaLipopolysaccharidesMiceMice, Inbred C57BLMyeloid Differentiation Factor 88Myosin-Light-Chain KinasePermeabilitySignal TransductionTight JunctionsToll-Like Receptor 4

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29157665

Citation

Nighot, Meghali, et al. "Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated By Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression." The American Journal of Pathology, vol. 187, no. 12, 2017, pp. 2698-2710.
Nighot M, Al-Sadi R, Guo S, et al. Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. Am J Pathol. 2017;187(12):2698-2710.
Nighot, M., Al-Sadi, R., Guo, S., Rawat, M., Nighot, P., Watterson, M. D., & Ma, T. Y. (2017). Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. The American Journal of Pathology, 187(12), 2698-2710. https://doi.org/10.1016/j.ajpath.2017.08.005
Nighot M, et al. Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated By Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. Am J Pathol. 2017;187(12):2698-2710. PubMed PMID: 29157665.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lipopolysaccharide-Induced Increase in Intestinal Epithelial Tight Permeability Is Mediated by Toll-Like Receptor 4/Myeloid Differentiation Primary Response 88 (MyD88) Activation of Myosin Light Chain Kinase Expression. AU - Nighot,Meghali, AU - Al-Sadi,Rana, AU - Guo,Shuhong, AU - Rawat,Manmeet, AU - Nighot,Prashant, AU - Watterson,Martin D, AU - Ma,Thomas Y, PY - 2017/03/13/received PY - 2017/08/07/revised PY - 2017/08/22/accepted PY - 2017/11/22/entrez PY - 2017/11/22/pubmed PY - 2017/12/1/medline SP - 2698 EP - 2710 JF - The American journal of pathology JO - Am J Pathol VL - 187 IS - 12 N2 - Lipopolysaccharides (LPSs) are a major component of the Gram-negative bacterial cell wall and play an important role in mediating intestinal inflammatory responses in inflammatory bowel disease. Although recent studies suggested that physiologically relevant concentrations of LPS (0 to 1 ng/mL) cause an increase in intestinal epithelial tight junction (TJ) permeability, the mechanisms that mediate an LPS-induced increase in intestinal TJ permeability remain unclear. Herein, we show that myosin light chain kinase (MLCK) plays a central role in the LPS-induced increase in TJ permeability. Filter-grown Caco-2 intestinal epithelial monolayers and C57BL/6 mice were used as an in vitro and in vivo intestinal epithelial model system, respectively. LPS caused a dose- and time-dependent increase in MLCK expression and kinase activity in Caco-2 monolayers. The pharmacologic MLCK inhibition and siRNA-induced knock-down of MLCK inhibited the LPS-induced increase in Caco-2 TJ permeability. The LPS increase in TJ permeability was mediated by toll-like receptor 4 (TLR-4)/MyD88 signal-transduction pathway up-regulation of MLCK expression. The LPS-induced increase in mouse intestinal permeability also required an increase in MLCK expression. The LPS-induced increase in intestinal permeability was inhibited in MLCK-/- and TLR-4-/- mice. These data show, for the first time, that the LPS-induced increase in intestinal permeability was mediated by TLR-4/MyD88 signal-transduction pathway up-regulation of MLCK. Therapeutic targeting of these pathways can prevent an LPS-induced increase in intestinal permeability. SN - 1525-2191 UR - https://www.unboundmedicine.com/medline/citation/29157665/Lipopolysaccharide_Induced_Increase_in_Intestinal_Epithelial_Tight_Permeability_Is_Mediated_by_Toll_Like_Receptor_4/Myeloid_Differentiation_Primary_Response_88__MyD88__Activation_of_Myosin_Light_Chain_Kinase_Expression_ DB - PRIME DP - Unbound Medicine ER -