title: Prostaglandins produced during class A scavenger receptor-mediated macrophage adhesion differentially regulate cytokine production.
abstract: 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 PLA2-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 PLA2and Src kinase but not PI3K. SR-A+/+macrophages cultured on gluc-collagen for 24 h secreted a similar amount of TNF-αand 2.5-fold more IL-10 than SR-A-/-macrophages. The inhibition of COX substantially increased TNF-αproduction but reduced IL-10 levels in SR-A+/+macrophages. These effects of COX inhibition were reversed by exogenous PGE2and 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.
authors.affiliation: Departments of *Pathology, Pharmacology and Toxicology, and Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Dejan M
authors.initials: DM
authors.lastname: Nikolic
authors.affiliation: Departments of *Pathology, Pharmacology and Toxicology, and Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Vadali
authors.affiliation: Departments of *Pathology, Pharmacology and Toxicology, and Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Beixiang
authors.initials: B
authors.lastname: He
authors.affiliation: Departments of *Pathology, Pharmacology and Toxicology, and Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Ware
authors.affiliation: Departments of *Pathology, Pharmacology and Toxicology, and Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kelly
authors.affiliation: Departments of *Pathology, Pharmacology and Toxicology, and Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA spost@uams.edu.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Post
keywords: PGE2; cyclooxygenase; inflammation; phospholipase A2