TNF-α stimulates activation of pro-MMP2 in human skin through NF-κB mediated induction of MT1-MMP

Yuan Ping Han, Tai Lan Tuan, Huayang Wu, Michael Warren Hughes, Warren L. Garner

Research output: Contribution to journalArticle

308 Citations (Scopus)

Abstract

Tumor necrosis factor-alpha (TNF-α) is an important mediator during the inflammatory phase of wound healing. Excessive amounts of pro-inflammatory cytokines such as TNF-α are associated with inflammatory diseases including chronic wounds. Matrix metalloproteinases (MMPs) are involved in matrix re-modeling during wound healing, angiogenesis and tumor metastasis. As with pro-inflammatory cytokines, high levels of MMPs have been found in inflammatory states such as chronic wounds. In this report we relate these two phenomena. TNF-α stimulates secretion of active MMP-2, a type IV collagenase, in organ-cultured full-thickness human skin. This suggests a mechanism whereby excess inflammation affects normal wound healing. To investigate this observation at the cellular and molecular levels, we examined TNF-α mediated activation of pro-MMP-2, induction of MT1-MMP, and the intracellular signaling pathways that regulate the proteinase in isolated human dermal fibroblasts. We found that TNF-α substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-α individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-α significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-α and collagen activate the NF-κB pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-κB is essential to induce MT1-MMP expression in fibroblasts after TNF-α exposure. First, SN50, a peptide inhibitor for NF-κB nuclear translocation, simultaneously blocked the TNF-α and collagen mediated MT1-MMP induction and pro-MMP-2 activation. Secondly, TNF-α induced IκB to breakdown in fibroblasts within the collagen lattice, a critical step leading to NF-κB activation. Lastly, a consensus binding site for p65 NF-κB (TGGAGCTTCC) was found in the 5′-flanking region of human mt1-mmp gene. Based on these results and previous reports, we propose a model to explain TNF-α activation of MMP-2 in human skin. Activation of NF-κB signaling in fibroblasts embedded in collagen induces mt1-mmp gene expression, which subsequently activates the pro-MMP-2. The findings provide a specific mechanism whereby TNF-α may affect matrix remodeling during wound healing and other physiological and pathological processes.

Original languageEnglish
Pages (from-to)131-139
Number of pages9
JournalJournal of Cell Science
Volume114
Issue number1
Publication statusPublished - 2001 Feb 15

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Matrix Metalloproteinase 14
Tumor Necrosis Factor-alpha
Skin
Matrix Metalloproteinase 2
Fibroblasts
Collagen
Wound Healing
Matrix Metalloproteinases
Membrane-Associated Matrix Metalloproteinases
Physiological Phenomena
Cytokines
Gene Expression
5' Flanking Region
Wounds and Injuries
Collagenases
Pathologic Processes
Collagen Type I

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

Han, Yuan Ping ; Tuan, Tai Lan ; Wu, Huayang ; Hughes, Michael Warren ; Garner, Warren L. / TNF-α stimulates activation of pro-MMP2 in human skin through NF-κB mediated induction of MT1-MMP. In: Journal of Cell Science. 2001 ; Vol. 114, No. 1. pp. 131-139.
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abstract = "Tumor necrosis factor-alpha (TNF-α) is an important mediator during the inflammatory phase of wound healing. Excessive amounts of pro-inflammatory cytokines such as TNF-α are associated with inflammatory diseases including chronic wounds. Matrix metalloproteinases (MMPs) are involved in matrix re-modeling during wound healing, angiogenesis and tumor metastasis. As with pro-inflammatory cytokines, high levels of MMPs have been found in inflammatory states such as chronic wounds. In this report we relate these two phenomena. TNF-α stimulates secretion of active MMP-2, a type IV collagenase, in organ-cultured full-thickness human skin. This suggests a mechanism whereby excess inflammation affects normal wound healing. To investigate this observation at the cellular and molecular levels, we examined TNF-α mediated activation of pro-MMP-2, induction of MT1-MMP, and the intracellular signaling pathways that regulate the proteinase in isolated human dermal fibroblasts. We found that TNF-α substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-α individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-α significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-α and collagen activate the NF-κB pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-κB is essential to induce MT1-MMP expression in fibroblasts after TNF-α exposure. First, SN50, a peptide inhibitor for NF-κB nuclear translocation, simultaneously blocked the TNF-α and collagen mediated MT1-MMP induction and pro-MMP-2 activation. Secondly, TNF-α induced IκB to breakdown in fibroblasts within the collagen lattice, a critical step leading to NF-κB activation. Lastly, a consensus binding site for p65 NF-κB (TGGAGCTTCC) was found in the 5′-flanking region of human mt1-mmp gene. Based on these results and previous reports, we propose a model to explain TNF-α activation of MMP-2 in human skin. Activation of NF-κB signaling in fibroblasts embedded in collagen induces mt1-mmp gene expression, which subsequently activates the pro-MMP-2. The findings provide a specific mechanism whereby TNF-α may affect matrix remodeling during wound healing and other physiological and pathological processes.",
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TNF-α stimulates activation of pro-MMP2 in human skin through NF-κB mediated induction of MT1-MMP. / Han, Yuan Ping; Tuan, Tai Lan; Wu, Huayang; Hughes, Michael Warren; Garner, Warren L.

In: Journal of Cell Science, Vol. 114, No. 1, 15.02.2001, p. 131-139.

Research output: Contribution to journalArticle

TY - JOUR

T1 - TNF-α stimulates activation of pro-MMP2 in human skin through NF-κB mediated induction of MT1-MMP

AU - Han, Yuan Ping

AU - Tuan, Tai Lan

AU - Wu, Huayang

AU - Hughes, Michael Warren

AU - Garner, Warren L.

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N2 - Tumor necrosis factor-alpha (TNF-α) is an important mediator during the inflammatory phase of wound healing. Excessive amounts of pro-inflammatory cytokines such as TNF-α are associated with inflammatory diseases including chronic wounds. Matrix metalloproteinases (MMPs) are involved in matrix re-modeling during wound healing, angiogenesis and tumor metastasis. As with pro-inflammatory cytokines, high levels of MMPs have been found in inflammatory states such as chronic wounds. In this report we relate these two phenomena. TNF-α stimulates secretion of active MMP-2, a type IV collagenase, in organ-cultured full-thickness human skin. This suggests a mechanism whereby excess inflammation affects normal wound healing. To investigate this observation at the cellular and molecular levels, we examined TNF-α mediated activation of pro-MMP-2, induction of MT1-MMP, and the intracellular signaling pathways that regulate the proteinase in isolated human dermal fibroblasts. We found that TNF-α substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-α individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-α significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-α and collagen activate the NF-κB pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-κB is essential to induce MT1-MMP expression in fibroblasts after TNF-α exposure. First, SN50, a peptide inhibitor for NF-κB nuclear translocation, simultaneously blocked the TNF-α and collagen mediated MT1-MMP induction and pro-MMP-2 activation. Secondly, TNF-α induced IκB to breakdown in fibroblasts within the collagen lattice, a critical step leading to NF-κB activation. Lastly, a consensus binding site for p65 NF-κB (TGGAGCTTCC) was found in the 5′-flanking region of human mt1-mmp gene. Based on these results and previous reports, we propose a model to explain TNF-α activation of MMP-2 in human skin. Activation of NF-κB signaling in fibroblasts embedded in collagen induces mt1-mmp gene expression, which subsequently activates the pro-MMP-2. The findings provide a specific mechanism whereby TNF-α may affect matrix remodeling during wound healing and other physiological and pathological processes.

AB - Tumor necrosis factor-alpha (TNF-α) is an important mediator during the inflammatory phase of wound healing. Excessive amounts of pro-inflammatory cytokines such as TNF-α are associated with inflammatory diseases including chronic wounds. Matrix metalloproteinases (MMPs) are involved in matrix re-modeling during wound healing, angiogenesis and tumor metastasis. As with pro-inflammatory cytokines, high levels of MMPs have been found in inflammatory states such as chronic wounds. In this report we relate these two phenomena. TNF-α stimulates secretion of active MMP-2, a type IV collagenase, in organ-cultured full-thickness human skin. This suggests a mechanism whereby excess inflammation affects normal wound healing. To investigate this observation at the cellular and molecular levels, we examined TNF-α mediated activation of pro-MMP-2, induction of MT1-MMP, and the intracellular signaling pathways that regulate the proteinase in isolated human dermal fibroblasts. We found that TNF-α substantially promoted activation of pro-MMP-2 in dermal fibroblasts embedded in type-I collagen. In marked contrast, collagen or TNF-α individually had little influence on the fibroblast-mediated pro-MMP-2 activation. One well-characterized mechanism for pro-MMP-2 activation is through a membrane type matrix metalloproteinase, such as MT1-MMP. We report that TNF-α significantly induced MT1-MMP at the mRNA and protein levels when the dermal fibroblasts were grown in collagen. Although the intracellular signaling pathway regulating mt1-mmp gene expression is still obscure, both TNF-α and collagen activate the NF-κB pathway. In this report we provide three sets of evidence to support a hypothesis that activation of NF-κB is essential to induce MT1-MMP expression in fibroblasts after TNF-α exposure. First, SN50, a peptide inhibitor for NF-κB nuclear translocation, simultaneously blocked the TNF-α and collagen mediated MT1-MMP induction and pro-MMP-2 activation. Secondly, TNF-α induced IκB to breakdown in fibroblasts within the collagen lattice, a critical step leading to NF-κB activation. Lastly, a consensus binding site for p65 NF-κB (TGGAGCTTCC) was found in the 5′-flanking region of human mt1-mmp gene. Based on these results and previous reports, we propose a model to explain TNF-α activation of MMP-2 in human skin. Activation of NF-κB signaling in fibroblasts embedded in collagen induces mt1-mmp gene expression, which subsequently activates the pro-MMP-2. The findings provide a specific mechanism whereby TNF-α may affect matrix remodeling during wound healing and other physiological and pathological processes.

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