Interleukin 1β and Prostaglandin E2 affect expression of DNA methylating and demethylating enzymes in human gingival fibroblasts.

Periodontitis is a common chronic inflammatory condition that results in increased levels of inflammatory cytokines and inflammatory mediators. In addition to oral disease and tooth loss, it also causes low-grade systemic inflammation that contributes to development of systemic conditions including cardiovascular disease, pre-term birth, diabetes and cancer. Chronic inflammation is associated with epigenetic change, and it has been suggested that such changes can alter cell phenotypes in ways that contribute to both ongoing inflammation and development of associated pathologies.

Zinc-binding protein-89 (ZBP-89) cooperates with NF-κB to regulate expression of matrix metalloproteinases (MMPs) in response to inflammatory cytokines.

Matrix metalloproteinases (MMPs) have both protective and pathological roles in inflammation, and transcriptional mechanisms are important in regulating physiological levels to maintain health. Zinc-binding protein-89 (ZBP-89) is a transcription factor with roles in regulating vital cellular processes, acting through complex interactions with other proteins to ensure appropriate expression of tightly regulated genes. ZBP-89 binds the MMP-3 promoter at a polymorphic (5A/6A) site along with NF-κB.

IL-4 inhibition of IL-1 induced Matrix metalloproteinase-3 (MMP-3) expression in human fibroblasts involves decreased AP-1 activation via negative crosstalk involving of Jun N-terminal kinase (JNK).

Matrix metalloproteinase-3 (MMP-3) over-expression is associated with tissue destruction in the context of chronic inflammation. Previous studies showed that IL-4 inhibits induction of MMP-3 by IL-1β, and suggested that AP-1 might be involved. Here we show that IL-1 induced binding of transcription factor AP-1 to the MMP-3 promoter consists primarily of c-Jun, JunB, and c-Fos and that binding of c-Jun and c-Fos is inhibited by the combination of cytokines while binding of Jun B is not.

Expression of transcription factor zinc-binding protein-89 (ZBP-89) is inhibited by inflammatory cytokines.

Zinc-binding protein-89 (ZBP-89; ZNF148, BERF-1, BFCOL-1) is a zinc-finger transcription factor of the Kruppel family. It has been shown to regulate the expression of a number of genes, acting as either an activator or repressor of gene expression, depending on the context. It is over-expressed in several cancers, but has been shown to be involved in apoptosis and to have a negative influence on cell growth in part by interactions with p53.

NF-kappaB and ZBP-89 regulate MMP-3 expression via a polymorphic site in the promoter.

A 5T/6T polymorphism in the human MMP-3 promoter affects gene expression and impacts the risk and/or severity of various pathological conditions. Chromatin immunoprecipitation (ChIP) in human fibroblasts homozygous for the 6T site demonstrate that it is bound by NF-kappaB and ZBP-89 transcription factors in its native chromatin. ChIP in COS-1 cells transfected with plasmids containing the 5T and 6T sites in the context of 2kb of the MMP-3 promoter showed that NF-kappaB p50 binds preferentially to the 6T site, while more ZBP-89 binding is detected to the 5T site.

Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARgamma activation in human gingival fibroblasts.

Background: Interleukin 4 (IL-4) has been shown to suppress interleukin-1 (IL-1) induced expression of matrix metalloproteinase-3 (MMP-3) in human synovial and gingival fibroblasts, but the mechanism of suppression has not been determined. Activators of peroxisome proliferator-activated receptor-gamma (PPARgamma) have been shown to inhibit cytokine induced expression of MMPs in other cell types, and IL-4 has been shown to activate PPARgamma by stimulating production of ligands through the lipoxygenase pathway. It has been suggested that PPARgamma may inhibit expression of MMPs by competing with transcription factor AP-1 for binding to a putative composite binding element in the promoters.

Interleukin-4 suppresses IL-1-induced expression of matrix metalloproteinase-3 in human gingival fibroblasts.

Background: In periodontitis, matrix metalloproteinase-3 (MMP-3, stromelysin 1) is present at increased levels in active disease sites compared to inactive or healthy sites, and the levels are correlated with clinical parameters and associated with progression of the disease. Interleukin (IL)-4 has been shown in human skin and synovial fibroblasts and articular chondrocytes to suppress IL-1-induced expression of MMP-3, but this has not been shown in human gingival fibroblasts. The objective of this study is to determine the effects of IL-4 on the IL-1-induced expression of MMP-3 in human gingival fibroblasts isolated from patients with periodontitis.

NF-kappaB binds to a polymorphic repressor element in the MMP-3 promoter.

A 5T/6T polymorphic site in the matrix metalloproteinase-3 (MMP-3) promoter has been identified as a repressor element involved in inhibiting induction of MMP-3 transcription by interleukin 1; and the 6T allele has been associated with decreased expression of MMP-3 as compared to the 5T allele. Zinc-binding protein-89 (ZBP-89) was cloned from a yeast one-hybrid assay via its ability to interact with this site, but when the protein was over-expressed, it resulted in activation of the MMP-3 promoter rather than repression. Here we show that in nuclear extracts isolated from human gingival fibroblasts stimulated with IL-1, this site is bound by p50 and p65 components of NF-kappaB in addition to ZBP-89, and that recombinant p50 binds preferentially to the 6T binding site.

Human gingival fibroblasts produce nitric oxide in response to proinflammatory cytokines.

Background: Although nitric oxide (NO) synthesis is increased in periodontal disease (PD), little is known about the possible sources of production by gingival tissues. In fact, gingival tissues from patients with periodontitis demonstrate greater levels of inducible nitric oxide (iNOS) expression than healthy tissue. Macrophages are the source of the iNOS expression, with endothelial cells also contributing.