Interferon-γ Coordinately Upregulates Matrix Metalloprotease (MMP)-1 and MMP-3, But Not Tissue Inhibitor of Metalloproteases (TIMP), Expression in Cultured Keratinocytes

Tamai, Katsuto; Ishikawa, Hiroyasu; Mauviel, Alain; Uitto, Jouni

doi:10.1111/1523-1747.ep12665857

Cited by 67 publications

(41 citation statements)

References 26 publications

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“…These results suggests that INF-γ may play an important role in preventing excessive connective tissue degradation in physiologic condition. But, these findings are not consistent with other report that IFN-γ upregulates the expression of the collagenase and stormelysin in cultured skin keratinocytes (Tamai et al, 1995). This report further emphasizes the cell-type specificity with respect to IFN-γ effects on the regulation of MMPs.…”

Section: Discussioncontrasting

confidence: 92%

Interferon-γ upregulates the stromelysin-1 gene expression by human skin fibroblasts in culture

Lee

Ryoo²,

Song³

1998

Exp Mol Med

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A b s t r a c tThe equilibrium between deposition and degradation of extracellular matrix(ECM) is essential to normal tissue developement and repair of wound or inflammatory responses. It has recently become apparent that several cytokines and growth factors are capable of modulating fibroblast proliferation and biosynthetic activity. To understand the role of these factors in connective tissue regulation, we examined the effect of interferon-( I F N -) on stromelysin-1 gene expres-sion in cultured human dermal fibroblasts. The steady-state levels of stromelysin-1 mRNA were increased in IFN-treated cultured dermal fibroblasts. In the CAT assay, the stromelysin-1 promoter activity was increased 2.8-fold compared with untreated control. Therfore IFNstimulates the stromelysin-1 promoter activity, resulting in transcriptional enhance-ment of gene expression. Transforming growth factor-( T G F -) showed the antagonistic action to the effects of IFNin cultured dermal fibroblasts. Furthermore, gel mobility shift assays demonstrated enhanced AP-1 binding activities in nuclear extracts from cells incubated with IFN-. These data suggest that IFNis an up-regulator and TGF-is a down regulator on the stromelysin-1 gene expression, respectively, and the AP-1 binding site may be necessary for gene response.Keywords: stromelysin-1, interferon-γ, AP-1, gene expression IntroductionThe matrix metalloproteinase (MMP)familly, which includes collagenase (MMP-1), gelatinase (MMP-2), stromelysins (MMP-3), matrilysin and metalloelastase, were structurally related zinc-dependent proteolytic enzymes, yet specific activities are divergent (Wo e s s n e r, 1990; McCachren, 1991;Mauviel, 1993). Stromelysin-1 and -2 are closely related, yet distinct from metalloproteinases, and both can degrade many non-collagenous connetive tissue macromolecules such as fibronectin, laminin, elastin, IgG, and proteoglycans (Chin et al,, 1985). Stromelysin-1-producing keratinocytes resided on the basement membrane, whereas stromelysin-2-producing keratinocytes were in contact with the dermal matrix (Saarialho-Kere et al. , 1993). Furthermore, stromelysin-1 expression was prominent in dermal fibroblasts, whereas no signal for stromelysin-2 was observed in any dermal cells (Saarialhokere et al., 1993). Beside participating in normal connective tissue homeostasis, development and remodeling, the proteolytic activity of matrix metalloproteinases contributes significantly to the tissue damage that occurs in chronic inflamatory disease, such as rheumatoid arthritis and osteoarthrtis (Pelletier et al., 1993), as well as tumor invasion (Martrisian, 1990).Metalloproteinases are produced by multiple cell types and typically, their expressions are tightly regulated and limied to periods of active remodelling. The cell typespecific expression of metalloproteinases is regulated by various factors, including cell-matrix interaction, growth factors and cytokines, lipid mediator, tumor promotors, and inflammatory agent such as bacterial lipopolysaccharide ( S a a r i a l h o...

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Section: Discussioncontrasting

confidence: 92%

Interferon-γ upregulates the stromelysin-1 gene expression by human skin fibroblasts in culture

Lee

Ryoo²,

Song³

1998

Exp Mol Med

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“…Although long-term exposure of SCC cells to IFN-g has been shown to inhibit proliferation of SCC cells (Schuger et al, 1990), its role in tumor invasion is not known. IFN-g has been shown to enhance expression of MMP-1 and MMP-3 and inhibit expression of MMP-9 by normal human keratinocytes (Tamai et al, 1995;MaÈ kelaÈ et al, 1998). In addition, IFN-g has been shown to augment TNF-a induced production of MMP-1 by dermal ®broblasts (Westermarck et al, 1995) and inhibit expression of MMP-1 and MMP-3 in response to interleukin-1 (Varga et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to normal human epidermal keratinocytes (Tamai et al, 1995), treatment of both UT-SCC-7 and A-5 cells with IFN-g potently inhibited expression of MMP-1 (Figure 1). The maximal inhibition of MMP-1 mRNA abundance noted with 100 U/ml of IFN-g was 72% in UT-SCC-7 cells and 87% in A-5 cells (Figure 1a, b).…”

Section: Expression Of Mmp-13 and Mmp-1 By Transformed Keratinocytes mentioning

confidence: 95%

“…TNF-a and TGF-b (Johansson et al, 1997b(Johansson et al, , 1999. Tumor in®ltrating lymphocytes in SCCs express IFN-g (Kim et al, 1995;Arany et al, 1998), which can inhibit proliferation of SCC cells (Schuger et al, 1990) and stimulate production of MMP-1 and MMP-3 by normal epidermal keratinocytes (Tamai et al, 1995). To elucidate the possible role of IFN-g in SCC invasion, we ®rst treated transformed keratinocytes with di erent concentrations of IFN-g and determined their MMP-13 and MMP-1 expression.…”

Section: Expression Of Mmp-13 and Mmp-1 By Transformed Keratinocytes mentioning

confidence: 99%

“…Tumor-in®ltrating lymphocytes in SCCs express interferon-g (IFN-g), a Th1 cell-derived cytokine, which inhibits proliferation of SCC cells (Kim et al, 1995;Arany et al, 1998). IFN-g also inhibits expression of type I collagen and elastin by dermal ®broblasts (KaÈ haÈ ri et al, 1990(KaÈ haÈ ri et al, , 1992 and upregulates MMP-1 and stromelysin-1 (MMP-3) expression in normal human epidermal keratinocytes (Tamai et al, 1995). In the present study, we show that IFN-g potently inhibits expression of MMP-13 and MMP-1, as well as invasion by transformed keratinocytes.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-γ is associated with activation of extracellular signal-regulated kinase-1,2 and STAT1

et al. 2000

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Collagenase-3 (MMP-13) is characterized by an exceptionally wide substrate speci®city and restricted expression. MMP-13 is speci®cally expressed by transformed human keratinocytes in squamous cell carcinomas in vivo and its expression correlates with their invasion capacity. Here, we show, that interferon-g (IFN-g) markedly inhibits expression of MMP-13 by human cutaneous SCC cells (UT-SCC-7) and by ras-transformed human epidermal keratinocytes (A-5 cells) at the transcriptional level. In addition, IFN-g inhibits collagenase-1 (MMP-1) expression in these cells. IFN-g abolished the enhancement of MMP-13 and MMP-1 expression by transforming growth factor-b (TGF-b) and tumor necrosis factor-a (TNF-a), and inhibited invasion of A-5 cells through type I collagen. IFN-g also rapidly and transiently activates extracellular signal-regulated kinase 1,2 (ERK1,2) and blocking ERK1,2 pathway (Raf/MEK1,2/ERK1,2) by speci®c MEK1,2 inhibitor PD98059 partially (by 50%) prevents Ser-727 phosphorylation of STAT1 and suppression of MMP-13 expression by IFN-g. Furthermore, Ser-727 phosphorylation of STAT1 by ERK1,2, or independently of ERK1,2 activation is associated with marked reduction in MMP-13 expression. These observations identify a novel role for IFN-g as a potent inhibitor of collagenolytic activity and invasion of transformed squamous epithelial cells, and show that inhibition of MMP-13 expression by IFN-g involves activation of ERK1,2 and STAT1. Oncogene (2000) 19, 248 ± 257.

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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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Interferon-γ Coordinately Upregulates Matrix Metalloprotease (MMP)-1 and MMP-3, But Not Tissue Inhibitor of Metalloproteases (TIMP), Expression in Cultured Keratinocytes

Cited by 67 publications

References 26 publications

Interferon-γ upregulates the stromelysin-1 gene expression by human skin fibroblasts in culture

Interferon-γ upregulates the stromelysin-1 gene expression by human skin fibroblasts in culture

Inhibition of collagenase-3 (MMP-13) expression in transformed human keratinocytes by interferon-γ is associated with activation of extracellular signal-regulated kinase-1,2 and STAT1

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

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