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

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.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). We hypothesize that TCDD mediates these pathological lesions by altering the expression of genes involved in matrix remodeling.Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade the protein components of the extracellular matrix. MMP expression is integral to processes in skin remodeling and inappropriate expression and activity of MMPs is associated with a variety of pathologies such as rheumatoid arthritis and tumor metastasis (4 -6). Regulation of MMPs occurs primarily at the levels of transcription and activity (7). Investigation into MMP gene expression have identified several cis-and trans-acting factors that are involved in MMP-1 transcriptional activation, including several AP-1 sites and PEA-3 elements, that contribute to MMP-1 gene expression (8, 9).The primary mechanism of TCDD-induced changes in gene expression is through activation of the aryl hydrocarbon receptor (AhR)/aryl hydrocarbon receptor nuclear translocator (Arnt) transcription pathway. 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.

Aryl Hydrocarbon Receptor Activation Inhibits Regenerative Growth

“…Furthermore, TCCD-enhanced expression of MMP-1, -9, and TIMP-3 in lung airway epithelial cells by microarray analysis, implying that MMP expression maybe a common endpoint for AHR pathway activation (Martinez et al, 2002). In normal human keratinocytes, TCDD induces MMP-1 expression, and cotreatment with all trans-retinoic acid enhanced the MMP-1 expression additively (Murphy et al, 2004), suggesting the cross-talk of AHR pathway with other signaling pathways. These studies correlate with the finding that ECM remodeling is impaired in the regenerating fins of TCDD exposed adult zebrafish (E. Andreasen, personal communication).…”

ERβ in CD4+ T Cells Is Crucial for Ligand-Mediated Suppression of Central Nervous System Autoimmunity

“…The interaction of AhR with key transcription factors is well described (31,32). Great evidence exists regarding the physical interaction between AhR and c-Maf that bind together and transactivate the Il10 promoter (28,33).…”

Differentiation-Specific Factors Modulate Epidermal CYP1–4 Gene Expression in Human Skin in Response to Retinoic Acid and Classic Aryl Hydrocarbon Receptor Ligands

“…TGM1 was not a differentially expressed gene in this microarray study, possibly due to differences in TCDD exposure time and differentiation state (10-day TCDD exposure; SIK cultures at Ϸ80% confluence). In confluent cultures derived from normal human epidermis, acute (hours) TCDD exposure induced matrix metalloproteinase-1 expression; this response was mediated by functional AP1 sites in the matrix metalloproteinase-1 gene (Murphy et al, 2004). The effects of TCDD on TGM mRNA developed over days and may be partly mediated by interactions of AP1 proteins with TGM1 or other regulatory genes.…”