U73122 inhibits the dephosphorylation and translocation of cofilin in activated macrophage-like U937 cells

Cofilin, an actin-binding protein, plays an important role in the migration , phagocytosis, and superoxide production of activated phagocytes through c ytoskeletal reorganization. In unstimulated phagocytes, cofilin is a major phosphoprotein. However, upon activation, the phosphoprotein is dephosphory lated and translocated from cytosol to plasma membranes. Only the unphospho rylated form of cofilin is an active form that binds actin, whereas the reg ulatory mechanisms of cofilin have not been elucidated. We found that 1-[6- [[17 beta -3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5 -dione (U73122), an inhibitor of phospholipase C (PLC), suppressed both ops onized zymosan (OZ)-induced dephosphorylation and translocation of cofilin in macrophage-like U937 cells at 4 muM concentration. OZ triggered an incre ase in inositol 1,4,5-trisphosphate (IP3), and U73122 inhibited it. 1-[6-[[ 17 beta -3-Methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-p yrrodione (U73343), which was employed as an inactive analogue, had no such inhibitory activities as did U73122. Furthermore, herbimycin A, an inhibit or of src-type tyrosine kinase, also inhibited OZ-triggered IP3 formation. These results suggest that the activity and localization of cofilin are reg ulated by PLC at the downstream of src-family tyrosine kinase. (C) 2001 Els evier Science Inc. All rights reserved.