Prostaglandins produced during class A scavenger receptor-mediated macrophage adhesion differentially regulate cytokine production.

Inflammation is associated with modification of the extracellular environment, changes in cytokine expression, and the accumulation of immune cells. Such modifications create ligands that support SR-A-mediated macrophage adhesion and retention. This may be particularly important in settings, such as atherosclerosis and diabetes, as modified lipoproteins and gluc-collagen are ligands for SR-A. SR-A-mediated adhesion requires the PLA-dependent generation of AA and its metabolism by 12/15 LOX. In contrast, the inhibition of the COX-dependent conversion of AA to PG had no effect on SR-A-mediated adhesion. In this study, macrophages were isolated from SR-A and SR-A mice and plated on gluc-collagen to test the hypothesis that COX-derived PGs are produced during SR-A-mediated adhesion and regulate macrophage function. SR-A-mediated binding to gluc-collagen induced a rapid but transient increase in PG production, which required the activation of PLA and Src kinase but not PI3K. SR-A macrophages cultured on gluc-collagen for 24 h secreted a similar amount of TNF- and 2.5-fold more IL-10 than SR-A macrophages. The inhibition of COX substantially increased TNF- production but reduced IL-10 levels in SR-A macrophages. These effects of COX inhibition were reversed by exogenous PGE and mimicked by specific antagonism of the EP4 receptor. Thus, in addition to the enhancement of macrophage adhesion, SR-A binding to gluc-collagen stimulates PG production, which in turn, differentially regulates the expression of inflammatory cytokines.