TGF-BETA-1-STIMULATED ADHESION OF HUMAN MONONUCLEAR PHAGOCYTES TO FIBRONECTIN AND LAMININ IS ABOLISHED BY IFN-GAMMA - DEPENDENCE ON ALPHA-5-BETA-1 AND BETA-2 INTEGRINS

Monocyte migration within the extravascular space of inflamed tissues is controlled by adhesion molecules and inflammatory cytokines. In thi s study, we analyzed the capacity of TGF-beta 1 and IFN-gamma to regul ate adhesion of human activated monocytes to fibronectin (FN) and to l aminin (LM), two components of the extracellular matrix. When cultured in the absence of any of these two stimuli, human monocytes underwent ''spontaneous activation'' and adhered to both FN and LM. Adhesion to FN was inhibited in the presence of alpha 5 and beta 1 integrin block ing antibodies, whereas beta 2 blocking antibody blocked attachment to LM. Exogenous TGF-beta 1 increased the adhesive ability of monocytes to FN and to LM, respectively, linked to the increase of alpha 5 and b eta 2 mRNA and protein synthesis levels. Moreover, an increase in alph a 5 expression at the monocyte cell surface was observed. In contrast, monocytes stimulated with exogenous IFN-gamma lost their capacity to bind to FN and this coincided with the down-regulation of surface alph a 5 expression which occurred at the posttranscriptional level of alph a 5 synthesis. Although IFN-gamma-treated monocytes also showed a decr eased ability to adhere to LM, no alteration of beta 2 mRNA levels, be ta 2 protein synthesis, and beta 2 cell surface expression was detecta ble, thus suggesting a modification of the functional state of surface beta 2 integrins, Furthermore, when stimulated with TGF-beta 1, IFN-g amma-pretreated monocytes reacquired the ability to bind to FN and LM. Conversely, IFN-gamma reduced adhesiveness to FN and LM of monocytes initially stimulated with TGF-beta 1. These in vitro adhesive-deadhesi ve responses of monocytes to TGF-beta 1 and IFN-gamma modulation may r eflect mononuclear phagocyte motility within sites of inflammation. (C ) 1996 Academic Press, Inc.