Transcriptional inhibition of stromelysin by interferon-? in normal human fibroblasts is mediated by the AP-1 domain

Abstract

The expression of the major matrix-degrading metalloproteinase, stromelysin (SL), is modulated by a variety of cytokines and growth factors. Interferon-gamma (IFN-gamma) is a potent modulator of SL expression, either inhibiting or activating expression in a cell-specific manner. We have investigated the mechanisms involved in the regulation of SL gene expression in cultured human fibroblasts by IFN-gamma. Reverse transcription-polymerase chain reaction (RT-PCR) assays confirmed the previously reported profound inhibitory response of SL mRNA expression to IFN-gamma [Amaldi et al., 1989]. For evaluation in transient gene expression assays, 1.2-kilobase (kb) pairs (-1214 to +14 relative to the transcription start site), and shorter, deletion mutant fragments of the SL promoter were cloned into appropriate chloramphenicol acetyltransferase transferase (CAT) expression vectors. The SL promoter along this region contains an active polyomavirus enhancer A-binding protein-3 (PEA-3) site at -216 and an activator protein-1 (AP-1) site at -70. Treatment of transfected neonatal foreskin fibroblasts with 300-500 U/ml IFN-gamma resulted in down-regulation of both basal and IL-1beta-induced CAT gene expression. IFN-gamma also decreased CAT expression when placed under the control of a synthetic multimeric AP-1 site construct. Gel-shift assay data indicate a decrease in specific binding to AP-1 oligonucleotide of nuclear extract from IFN-gamma and PMA/IFN-gamma-treated cells. The suppression of SL expression by IFN-gamma, in human fibroblasts therefore is mediated through the AP-1 element.

Epstein‐Barr virus latent membrane protein 1 induces the matrix metalloproteinase‐1 promoter via an Ets binding site formed by a single nucleotide polymorphism: Enhanced susceptibility to nasopharyngeal carcinoma

“…Recently, critical sites in the MMP3 promoter were identified as AP1 and Ets binding sites. 54,55 As shown in Figure 3, MMP3 expression in LMP1-transfected cells was suppressed by Ets-DN and AP1-DN. Besides MMP3, MMP1 expression in LMP1-transfected cells was suppressed by expression of AP1-DN and Ets-DN forms.…”

IFN-γ Up-Regulates IL-18 Gene Expression Via IFN Consensus Sequence-Binding Protein and Activator Protein-1 Elements in Macrophages

“…Lewis et al (44) reported that IFN-␥ decreased AP-1-binding activity of stromelysin gene in human fibroblasts, but it was reported by Lee et al (45) that IFN-␥ enhanced AP-1-binding activity of stromelysin-1 gene in human skin fibroblasts. In our study using murine macrophages, IFN-␥ apparently enhanced AP-1-binding complex containing c-Jun and c-Fos, and it also increased the expression of c-Jun and c-Fos in nucleus, as reported before (46).…”

Matrix metalloproteinase pattern in celiac duodenal mucosa

“…Since a correlation between the magnitude of villous atrophy and that of enterocyte apoptosis has been shown previously in untreated CD patients, 26 it is conceivable that, by degrading either interstitial ECM or basement membranes, 12 MMP-12 ultimately leads to the collapse of villous architecture and subsequent enterocyte shedding to the lumen. Furthermore, since MMP expression is highly dependent on cytokines 27,28 and gluten exposure in patients with CD rapidly elicits high levels of Th-1 cytokines, such as IFN-g, IL-2 and TNF-a, 13,14 we simultaneously determined the levels of IFN-g and TNF-a. Our results confirm a strong upregulation of IFN-g in active CD but not of TNF-a, the latter being in accordance with recent findings by Forsberg et al 29 who showed a suppression of TNF-a mRNA in this condition.…”