Activation of p38 MAPK is required for ligand‐induced Class A scavenger receptor expression

Abstract

Class A Scavenger Receptors (SR-A) mediate the internalization of a variety of polyanionic proteins (e.g., modified LDL, bacteria) and adhesion to modified extracellular matrix. Previous studies demonstrated that SR-A expression and function are regulated by SR-A ligands. In this study, we determined the importance of specific intracellular signaling pathways in ligand-dependent regulation of SR-A expression. For this, we incubated mouse peritoneal macrophages (MPM) with the SR-A specific ligand AcLDL in the presence or absence of specific signaling pathway inhibitors. Activation of specific signaling proteins and changes in SR-A protein were assessed by western blotting cell lysates with antibodies to SR-A or the activated-state of specific signaling proteins. We found that incubating MPM with acetylated-LDL (AcLDL), but not native LDL, for 24 hrs dose-dependently increased SR-A expression. Incubation of MPM with AcLDL was associated with a rapid activation of the mitogen activated protein kinases (MAPK) extracellular signal-regulated kinase (ERK1/2), cJun N-terminal kinase (JNK), and p38 kinase. To determine the importance of MAPK activation in ligand-dependent regulation of SR-A expression, MPM were treated with specific inhibitors of ERK1/2, JNK, and p38 prior to incubating with AcLDL. Ligand-induced SR-A expression was not affected by either ERK1/2 or JNK inhibitors but was abolished by pretreating cells with the p38 kinase inhibitor. Overall, these results indicate that ligand binding to SR-A activates multiple intracellular signaling pathways. However, ligand-induced SR-A expression specifically requires activation of p38 MAPK. (Supported by grants from the NIH and AHA)