Involvement of CD11b integrin in the alteration of metabolic factors after phorbol ester stimulation of human myeloid leukemia cells

The human U937 myeloid leukemia cell line represents an in vitro model for monocyte/macrophage-like differentiation and retrodifferentiation [1-5]. A variety of molecular effects by differentiation-inducing agents such as the phorbol ester derivate 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on cell adherence and filament expression in U937 cells have been extensively characterized [6,7]. Thus, the non-adherent growing and like tumor cells autonomously proliferating U937 wild-type population can be stimulated by TPA to differentiate along the monocyte/macrophage pathway which is associated with induced adherence and cessation of cell growth. The TPA-mediated attachment of differentiating U937 cells is accompanied by an enhanced expression of the β2-integrins CD11a, CD11c, CD18, and particularly CD11b [6]. These integrin compounds are cell membrane-associated glycoproteins whereby CD11a, CD11b and CD11c represent separate α-subunits to associate with the common β-subunit CD18, respectively. The appropriate heterodimeric protein complex forms a functional β2-integrin which is involved in the formation of cell-to-cell contacts and intercellular communication processes [8]. Moreover, junctional adhesion molecules including ICAMs can associate through their extracellular domains with functional β2-integrins on adjacent cells, contributing for example to the regulation of leukocyte-endothelial cell interactions [9].Previous work has demonstrated that a differentiation-defective subclone of the U937 cell line, termed TUR (TPA-U937-resistant), fails to express significant levels of CD11b after TPA treatment [10]. Concomitantly, these human TUR leukemia cells are unable to attach and continue to proliferate in response to a phorbol ester stimulation [11] indicating that CD11b displays a differentiation-associated function beyond an involvement in the regulation of cell attachment. Indeed, previous work has demonstrated that a down-modulation of the CD11b integrin fails to de