STUDIES WITH WORTMANNIN AND CYTOCHALASINS SUGGEST A PIVOTAL ROLE OF PHOSPHATIDYLINOSITOLS IN THE REGULATION OF TIGHT JUNCTION INTEGRITY

Wortmannin, a selective inhibitor of phosphatidylinositol 3-kinase (P1 3K), was found to give a dose and time-dependent, bimodal effect-initi al increase, followed by decrease on the tight junction integrity of M DCK-1 monolayers, as assessed by electrical resistance measurement of the epithelia. Moreover, dihydrocytochalasin B inhibited the wortmanni n-induced alteration, whereas cytochalasin B had a negligible influenc e on the wortmannin effect. Wortmannin was also found to cause changes in the cytoskeleton structure. These alterations were also seen when wortmannin was combined with cytochalasin B. However, in accordance wi th the electrical resistance measurements, dihydrocytochalasin B was a ble to abolish wortmannin-induced filamentous (F-) actin changes. Thes e findings suggest that the P13K, phosphatidylinositols, and filamento us actin rearrangements, in combination, play an important role in the modulation of the junctional integrity.