Activation of Extracellular Signal-regulated Kinase 1/2 Inhibits Type I Collagen Expression by Human Skin Fibroblasts

Reunanen, Niina; Foschi, Marco; Han, Jiahuai; Kähäri, Veli‐Matti

doi:10.1074/jbc.c000175200

Cited by 56 publications

(60 citation statements)

References 40 publications

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“…In human neutrophils, enhanced ERK1/2 activity increases GM-CSF mRNA stability, thus contributing to guarantee the presence of this important growth factor (43). By contrast, ERK1/2 activity was found to correlate with reduced type I collagen mRNA stability in skin fibroblasts (44). This latter mechanism may provide the inhibitory signal on extracellular matrix deposition during wound repair and tumor growth.…”

Section: Discussionmentioning

confidence: 93%

ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation

Pastore

Mascia

Mariotti

et al. 2005

The Journal of Immunology

166

172

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Resident cell populations of the skin contribute to the inflammatory response by producing an array of chemokines, which attract leukocytes from the circulation. TNF-α is a major inducer of proinflammatory mediators in keratinocytes. We have recently observed that epidermal growth factor receptor (EGFR) signaling affects TNF-α-driven chemokine expression in epidermal keratinocytes, and its functional impairment increases the levels of crucial chemoattractants such as CCL2/MCP-1, CCL5/RANTES, and CXCL10/IFN-γ-inducible protein-10. In this study, we report evidence that EGFR-dependent ERK1/2 activity is implicated in this mechanism. Abrogation of ERK1/2 activity with specific inhibitors increased chemokine expression in keratinocytes by enhancing mRNA stabilization. In mouse models, inflammatory response to irritants and T cell-mediated contact hypersensitivity were both aggravated when elicited in a skin area previously treated with an EGFR or a MAPK kinase 1/2 inhibitor. In contrast, impairment of p38αβ MAPK phosphorylation markedly attenuated these responses. Our data indicate that EGFR-dependent ERK1/2 activity in keratinocytes takes part to a homeostatic mechanism regulating inflammatory responses, and emphasize the distinct role of MAPKs as potential targets for manipulating inflammation in the skin.

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Section: Discussionmentioning

confidence: 93%

ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation

Pastore

Mascia

Mariotti

et al. 2005

The Journal of Immunology

166

172

View full text Add to dashboard Cite

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“…Interestingly, acrolein stimulates release of inflammatory cytokines and can alter cellular repair processes by impairing fibroblast function (45). Previous evidence of a role for ERK in matrix remodeling has also been shown using human fibroblasts, in which ERK was associated with inhibition of collagen type I expression (46). Additional studies will identify transcription factors involved in the airway response to cigarette smoke.…”

Section: Discussionmentioning

confidence: 96%

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

158

172

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The interstitial collagenase matrix metalloproteinase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERKdependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.

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“…Functional AP-1 elements have been found in the promoter regions of genes encoding IL-1␤, VEGF-A, and MMP1, and p42/p44 MAPKs were shown to activate transcription through these AP-1 elements (44 -46). Although p42/p44 MAPKs are also involved in the down-regulation of type 1 collagen gene expression by basic fibroblast growth factor, platelet-derived growth factor, and ceramide (47,48), PD98059 was unable to block Cyr61-suppression of Col1␣1 expression (Fig. 6B).…”

Section: Discussionmentioning

confidence: 99%

The Angiogenic Factor Cyr61 Activates a Genetic Program for Wound Healing in Human Skin Fibroblasts

Chen

Lau

2001

Journal of Biological Chemistry

265

224

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Cyr61 is a heparin-binding, extracellular matrix-associated protein of the CCN family, which also includes connective tissue growth factor, Nov, WISP-1, WISP-2, and WISP-3. Cyr61 is capable of multiple functions, including induction of angiogenesis in vivo. Purified Cyr61 mediates cell adhesion and induces adhesive signaling, stimulates cell migration, enhances cell proliferation, and promotes cell survival in both fibroblasts and endothelial cells. In this study, we have used cDNA array hybridization to identify genes regulated by Cyr61 in primary human skin fibroblasts. The Cyr61-regulated genes fall into several groups known to participate in processes important for cutaneous wound healing, including: 1) angiogenesis and lymphogenesis (VEGF-A and VEGF-C); 2) inflammation (interleukin-1␤); 3) extracellular matrix remodeling (MMP1, MMP3, TIMP1, uPA, and PAI-1); and 4) cell-matrix interactions (Col1␣1, Col1␣2, and integrins ␣ 3 and ␣ 5 ). Cyr61-mediated gene expression requires heparin binding activity of Cyr61, cellular de novo transcription, and protein synthesis and is largely dependent on the activation of p42/p44 MAPKs. Cyr61 regulates gene expression not only in serum-free medium but also in fibroblasts cultured on various matrix proteins or in the presence of 10% serum. These effects of Cyr61 can be sustained for at least 5 days, consistent with the time course of wound healing in vivo. Interestingly, Cyr61 can interact with transforming growth factor-␤1 to regulate expression of specific genes in an antagonistic, additive, or synergistic manner. Furthermore, we show that the Cyr61 gene is highly induced in dermal fibroblasts of granulation tissue during cutaneous wound repair. Together, these results show that Cyr61 is inducibly expressed in granulation tissues after wounding and that Cyr61 activates a genetic program for wound repair in skin fibroblasts. We propose a model in which Cyr61 integrates its activities on endothelial cells, fibroblasts, and macrophages to regulate the processes of angiogenesis, inflammation, and matrix remodeling in the context of cutaneous wound healing.

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Activation of Extracellular Signal-regulated Kinase 1/2 Inhibits Type I Collagen Expression by Human Skin Fibroblasts

Cited by 56 publications

References 40 publications

ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation

ERK1/2 Regulates Epidermal Chemokine Expression and Skin Inflammation

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

The Angiogenic Factor Cyr61 Activates a Genetic Program for Wound Healing in Human Skin Fibroblasts

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