STAT1 activation during monocyte to macrophage maturation: role of adhesion molecules

Human monocytes isolated from peripheral blood of healthy donors show a tim e-dependent differentiation into macrophages upon in vitro cultivation, clo sely mimicking their in vivo migration and maturation into extravascular ti ssues. The mediator(s) of this maturation process has not been yet defined. We investigated the involvement of signal transducers and activators of tr anscription (STAT) factors in this phenomenon and reported the specific, ti me-dependent, activation of STAT1 protein starting at day 0/1 of cultivatio n and maximally expressed at day 5, STAT1 activity was evident on the STAT binding sequences (SBE) present in the promoters of genes which are up-regu lated during monocyte to macrophage maturation such as Fc gamma RI and ICAM -1, and in the promoter of the transcription factor IFN regulatory factor-1 , Moreover, the effect of cell adhesion to fibronectin or laminin was studi ed to investigate mechanisms involved in STAT1 activation. Compared with mo nocytes adherent on plastic surfaces, freshly isolated cells allowed to adh ere either to fibronectin- or laminin-coated flasks exhibited an increased STAT1 binding activity both in control and in IFN-gamma-treated cells. The molecular events leading to enhanced STAT1 activation and cytokine responsi veness concerned both Y701 and S727 STAT1 phosphorylation, Exogenous additi on of transforming growth factor-beta, which exerts an inhibitory effect on some monocytic differentiation markers, inhibited macrophage maturation, i ntegrin expression and STAT1 binding activity. Taken together these results indicate that STAT1 plays a pivotal role in the differentiation/maturation process of monocytes as an early transcription factor initially activated by adherence and then able to modulate the expression of functional genes, such as ICAM-1 and Fc gamma RI.