Interaction between the Aryl Hydrocarbon Receptor and Retinoic Acid Pathways Increases Matrix Metalloproteinase-1 Expression in Keratinocytes

Kyle A Murphy,Caren M Villano,Ruth Dorn,Lori A White

doi:10.1074/jbc.m402168200

Abstract

Exposure to the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a variety of pathological lesions in humans via activation of the aryl hydrocarbon receptor (AhR) pathway. It has become apparent that this pathway interacts with a variety of signaling pathways that are believed to be involved in mediating TCDD/AhR biological effects. Our hypothesis is that TCDD mediates these pathological lesions by directly altering the expression of genes involved in matrix deposition and remodeling and that the retinoic acid signaling pathway is involved in modulating TCDD-induced effects. Therefore, we examined the effect of TCDD and all-trans retinoic acid (atRA) on the expression of matrix metalloproteinase-1 (MMP-1, interstitial collagenase), one of the proteolytic enzymes that degrade type I collagen, in normal human keratinocytes. The data show that TCDD exposure results in increased MMP-1 expression in keratinocytes that is further enhanced by co-treatment with all-trans retinoic acid. TCDD-induced expression of MMP-1 appears to be mediated through two AP-1 elements in the proximal promoter of the MMP-1 gene. However, retinoic acid-mediated induction of keratinocyte MMP-1 is a result of both promoter activation and increased mRNA stability. These findings are the first to demonstrate TCDD-induced expression of MMP-1 and to demonstrate interactions between the TCDD/AhR and retinoic acid pathways on MMP-1 expression.

Highlights

Exposure to the polycyclic aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)1 results in a number of pathological lesions involving matrix deposition and tissue remodeling, including prostate and mammary tubule morphogenesis, palatal development, and tumor promotion (1–3)
Northern Blot Analysis of Matrix metalloproteinases (MMPs)-1 and CYP1A1 Expression—To determine the effect of TCDD and all-trans retinoic acid treatment on MMP-1 expression in NHK, Northern blots of poly(A)ϩ RNA, isolated from NHK cultures exposed to TCDD (10Ϫ8 M), atRA (10Ϫ6 M), atRA ϩ TCDD or vehicle control (Me2SO), were hybridized with probes to human MMP-1 as well as probes for three known aryl hydrocarbon receptor (AhR)-responsive genes (CYP1A1, CYP1B1, and PAI-2) (Fig. 1)
These data demonstrate that TCDD and atRA pathways interact to modulate gene expression, and that this interaction inhibits the expression of CYP1A1, while activating the expression of MMP-1 and PAI-2

Summary

Introduction

Exposure to the polycyclic aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in a number of pathological lesions involving matrix deposition and tissue remodeling, including prostate and mammary tubule morphogenesis, palatal development, and tumor promotion (1–3). AhR and its dimerization partner, Arnt, are members of the basic helix-loop-helix PAS (bHLH-PAS) domain family of transcription factors Proteins in this family have diverse biological roles ranging from regulation of development, hypoxia signaling, and circadian rhythms (reviewed in Ref. 10). Studies of AhR/Arnt and TCDD have focused on heterodimer ability to activate transcription of xenobiotic-metabolizing genes including members of the cytochrome p450 (CYP450) family of monooxygenase enzymes (14, 16), as well as genes unrelated to xenobiotic metabolism. These include genes encoding proteins involved in growth control, cytokines, nuclear transcription factors, and regulators of extracellular matrix proteolysis (17, 18). We present data that show this pathway interacts with the retinoic acid signaling pathway to alter the expression of MMP-1

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Results

Conclusion