Interferon-beta induces metalloproteinase mRNA expression in human fibroblasts. Role of activator protein-1.

Sciavolino, Peter J.; Lee, T H; Vilček, Ján

doi:10.1016/s0021-9258(17)31851-3

Cited by 38 publications

References 49 publications

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

Lewis¹,

Amento²,

Unemori³

1999

J. Cell. Biochem.

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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.

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

Lewis¹,

Amento²,

Unemori³

1999

J. Cell. Biochem.

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Matrilysin expression in human prostate carcinoma

et al. 1996

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The metalloproteinases, a multigene family of metal-requiring enzymes, have been suggested to play a role in tumor invasion and metastasis. Previously, we demonstrated that human primary prostate tumors express higher levels of matrilysin and gelatinase A mRNA than normal prostate does. In the study presented here, we used in situ hybridization and immunohistochemical staining of serial sections of paraffin-embedded primary prostate tumors to compare the sites of matrilysin and gelatinase A expression and protein localization. These results confirmed the epithelial nature of matrilysin expression and protein localization. In contrast, gelatinase A mRNA was localized to the interstitial stroma, whereas the protein was associated with the epithelial tumor cells. In situ hybridization was also used to demonstrate that gelatinase B expression was restricted to macrophages infiltrating the tumors. Proteins isolated from an additional set of frozen tumor specimens were analyzed by western blotting to determine the relative amounts of matrilysin in the active and proenzyme forms. The western analyses demonstrated that in all cases in which matrilysin was detected, at least some of the enzyme was in the active form. These results are discussed with respect to the possible role these enzymes may play in prostate tumor progression.

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Constitutive collagenase‐1 synthesis through MAPK pathways is mediated, in part, by endogenous IL‐1α during fibrotic repair in corneal stroma

Jung

Huh

Fini

2007

J of Cellular Biochemistry

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Collagenase-1 is a protease expressed by active fibroblasts that is involved in remodeling of the extracellular matrix (ECM). In this study, we characterize the intracellular signaling mechanism of collagenase-1 production by IL-1alpha in subcultured normal fibroblasts (NF) from uninjured normal corneas, compared to that in repair wound fibroblasts (WF). In NF, collagenase-1 was induced specifically after the exogenous addition of IL-1alpha via activation of ERK and p38MAPK. Collagenase-1 expression was strongly suppressed upon treatment with either a MEK or p38MAPK inhibitor. In contrast, repair WF constitutively synthesized both IL-1alpha and collagenase-1. Combined treatment with both mitogen-activated protein kinase (MAPK) inhibitors dramatically reduced collagenase-1 synthesis, while individual MEK1 or p38 inhibitors weakly modulated the collagenase-1 level. The results indicate that both pathways are crucial in the regulation of collagenase-1 synthesis. Furthermore, an IL-1alpha receptor antagonist (IL-1ra) could not abolish constitutive collagenase-1 synthesis, even at high doses, suggesting that other cytokines/factors are additionally involved in this process. We propose that induction of collagenase-1 by IL-1alpha in both WF and NF depends on a unique combination of cell type-specific signaling pathways.

show abstract

Interferon-beta induces metalloproteinase mRNA expression in human fibroblasts. Role of activator protein-1.

Cited by 38 publications

References 49 publications

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

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

Matrilysin expression in human prostate carcinoma

Constitutive collagenase‐1 synthesis through MAPK pathways is mediated, in part, by endogenous IL‐1α during fibrotic repair in corneal stroma

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