Phorbol esters induce differentiation of U-937 human promonocytic cells in the absence of LFA-1/ICAM-1-mediated intercellular adhesion.

Intercellular adhesions which occur during the mononuclear phagocyte differentiation are predominantly mediated by the lymphocyte-function-associated antigen-1 (LFA-1) family and the intercellular-adhesion molecule-1 (ICAM-1) which is a ligand for LFA-1. Thus, differentiation of U-937 promonocytic cells induced by phorbol esters occurs concomitantly with intercellular LFA-1/ICAM-1-dependent cluster formation. Since these homotypic adhesions can be inhibited by monoclonal antibodies (mAb) directed to either LFA-1 or ICAM-1, we have analyzed whether the lack of cell-cell adhesions impairs the differentiation process. Treatment of U-937 cells with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate in the presence of mAb to LFA-1 or ICAM-1 antigens yielded cells free from homotypic adhesions but differentiated as evidenced by their decreased proliferation and enhanced capacity for generation of superoxide anion. In addition, expression of the CD11c antigen was increased, whereas the transferrin receptor disappeared from the cell surface. Vimentin gene transcription was also greatly augmented as opposed to a clear diminution in the levels of c-myc and ornithine decarboxylase transcripts. These results clearly demonstrate that phorbol esters can induce differentiation of monocytic cells independently of cell-cell adhesion.