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CELLULAR AND MOLECULAR

Role of Phospholipase C- in the Modulation of Epithelial Tight Junction Permeability

Department of Pharmacology, School of Medicine (P.D.W.), Division of Medicinal Chemistry and Natural Products, School of Pharmacy (H.O.), and Division of Drug Delivery and Disposition, School of Pharmacy (D.R.T.), University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

The results presented in this study establish an association between phospholipase C- (PLC-) and tight junction permeability across Madin-Darby canine kidney (MDCK) cell monolayers, an in vitro model for epithelial tissue. These results further show that PLC- modulates tight junction permeability by affecting actin filament organization. Hexadecylphosphocholine (HPC) inhibited PLC- and increased tight junction permeability in MDCK cells. Interestingly, the analogs of HPC, a series of alkylphosphocholines containing various lengths of linear alkyl chains, inhibited PLC- and increased tight junction permeability with a wide range of potency. The potency of alkylphosphocholines as enhancers of tight junction permeability significantly correlated (p < 0.05) with their potency as PLC- inhibitors. U73122, a steroid derivative that is structurally unrelated to alkylphosphocholines, inhibited PLC- and increased tight junction permeability with potencies that fit into the correlation observed for the alkylphosphocholine series. U73122 and HPC induced disorganization of actin filaments in MDCK cell monolayers. The potencies to cause disorganization of actin filaments were consistent with the potencies of these agents as inhibitors of PLC- and enhancers of tight junction permeability. Furthermore, ATP, an activator of PLC-, attenuated U73122-induced increase in tight junction permeability as well as disorganization of actin filaments. These results provide strong evidence that PLC- inhibition leads to increased tight junction permeability across MDCK cell monolayers through disorganization of actin filaments.

Address correspondence to: Dr. Dhiren R. Thakker, Division of Drug Delivery and Disposition, School of Pharmacy, CB#7360, 303B Beard Hall, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360. E-mail: dhiren_thakker{at}unc.edu

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