Suppression of Constitutive but Not IL-1β-Inducible Expression of Monocyte Chemoattractant Protein-1 in Mesangial Cells by Retinoic Acids: Intervention in the Activator Protein-1 Pathway

Abstract

Abstract. Retinoic acid regulates a wide range of biologic processes, including inflammation. This study investigated the effect of all-trans-retinoic acid (t-RA) on the constitutive and cytokine-inducible expression of monocyte chemoattractant protein 1 (MCP-1) in rat mesangial cells. Serum-deprived mesangial cells exhibited substantial levels of MCP-1 mRNA, and the expression was markedly upregulated by interleukin-1β (IL-1β). Pretreatment with t-RA abrogated the constitutive mRNA expression but did not inhibit the IL-1β-inducible expression. The similar effects were observed by 9-cis-RA. The suppressive effect of t-RA required retinoic acid receptors. t-RA did not affect the stability of MCP-1 mRNA, indicating that its suppressive effect was at the transcriptional level. Experiments that used pharmacologic and genetic inhibitors showed that the IL-1β-inducible MCP-1 expression was dependent on nuclear factor-κB (NF-κB) and independent of activator protein 1 (AP-1). In contrast, the constitutive expression of MCP-1 was dependent on both NF-κB and AP-1. t-RA substantially inhibited the constitutive activity of AP-1 but did not inhibit NF-κB activity in mesangial cells. These data suggested that (1) constitutive and IL-1β-inducible expression of MCP-1 was differently regulated by AP-1 and NF-κB and (2) t-RA inhibited selectively the constitutive expression of MCP-1 via intervention in the AP-1 pathway.