Heat Shock-Induced Matrix Metalloproteinase (MMP)-1 and MMP-3 Are Mediated through ERK and JNK Activation and via an Autocrine Interleukin-6 Loop

Background: Cholesterol is a major component of specialized membrane microdomains known as lipid rafts or caveolae, which modulate the fluidity of biological membranes. Membrane cholesterol therefore plays an important role in cell signaling and vesicular transport. Objective: In this study, we investigated the effects of cholesterol on matrix metalloproteinase-1 (MMP-1) expression in human dermal fibroblasts. Methods: MMP-1 mRNA and protein expression were determined by RT-PCR and Western blotting, respectively. AP-1 DNA binding activity was detected by electrophoretic mobility shift assays. The amount of cholesterol was analyzed by cholesterol assay kit. Results: We observed that MMP-1 mRNA and protein expression was dose-dependently decreased by cholesterol treatment. In contrast, cholesterol depletion by a cholesterol depletion agent, methyl-beta-cyclodextrin (MβCD) in human dermal fibroblasts, increased MMP-1 mRNA and protein expression in a dose-dependent manner. Also, we investigated the regulatory mechanism of MβCD-induced MMP-1 expression: cholesterol depletion by MβCD, activated ERK1/2 and JNK, but not p38 MAPK cascade, and it also significantly increased c-Jun phosphorylation, c-Fos expression and activator protein-1 binding activity. Furthermore, the inhibition of ERK or JNK with specific chemical inhibitors prevented MβCD-induced MMP-1 expression, which indicates that ERK and JNK play an important role in cholesterol depletion-mediated MMP-1 induction. In addition, MβCD-induced phosphorylation of ERK and JNK and MMP-1 expression were suppressed by cholesterol repletion. Conclusion: Our results suggest that cholesterol regulates MMP-1 expression through the control of ERK and JNK activity in human dermal fibroblasts. (Ann Dermatol 22(4) 379∼388, 2010)

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“…TNF alpha-induced and heat-induced MMP-1 expression is mediated through ERK1/2 and JNK activation 15,35 .…”

Section: Discussionmentioning

confidence: 99%

Cholesterol, a Major Component of Caveolae, Down-regulates Matrix Metalloproteinase-1 Expression through ERK/JNK Pathway in Cultured Human Dermal Fibroblasts

et al. 2010

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“…Similar to our results in cardiac fibroblasts, MMP-3 was attenuated by inhibition of ERK and JNK MAP kinases in human skin fibroblasts. [23] These fingerprints of MMP regulation by pro-inflammatory cytokines in specific cell types and experimental conditions may reflect interactions in upstream intracellular signaling pathways converging on elements of the MMP gene promoters.…”

Section: Discussionmentioning

confidence: 99%

Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts

Brown

Jones

Laird

et al. 2007

Biochemical and Biophysical Research Communications

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We sought to define the relationship between cytokine stimulated release of matrix metalloproteinases (MMPs) and cell migration using adult rat cardiac fibroblasts. Interleukin-1β (IL-1β) increased release of MMP-2, 3, and 9, and TIMP-1, by 3-6-fold, measured by immunoblotting and gel zymography. Tumor necrosis factor-α (TNFα) augmented IL-1 stimulated release of MMP-9, but not MMP-2 or -3. Transforming growth factor-β1 (TGFβ1) attenuated all the responses to IL-1β. IL-1β was also the most robust stimulus of adult rat cardiac fibroblast migration, measured in Boyden chamber assays. The combination of IL-1β plus TNFα substantially enhanced migration, whereas TGFβ1 strongly inhibited the migratory response to IL-1β. The pan-selective MMP inhibitor GM 6001 effectively blocked IL-1β stimulated migration. Pharmacologic inhibitors selective for ERK, JNK, and p38 MAP kinase pathways inhibited the IL-1β regulation of individual MMPs. Increased MMP activity associated with migration of cardiac fibroblasts may be important determinants of cytokine-directed remodeling of injured myocardium.

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“…2) Of note, excess expression of MMPs in keratinocytes and dermal fibroblasts, under a variety of stress conditions such as UV radiation (UVR), and heat-shock, 3) which both are closely associated to the aged skin phenotypes, 4,5) contributes to the degradation of ECM proteins, leading to wrinkle formation in photo-aged skin.…”

Section: )mentioning

confidence: 99%

Nobiletin Suppresses MMP-9 Expression through Modulation of p38 MAPK Activity in Human Dermal Fibrobalsts

Kim

Korm

Kim

et al. 2014

Biological & Pharmaceutical Bulletin

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We aimed to identify a novel flavonoid from the in-house natural products to suppress matrix metalloproteases (MMPs), which is responsible for degradation of collagen and other extracellular matrix proteins. Total eight natural products were screened for identification of a novel MMP-9 suppressor using MMP-9 reporter system, where the prompt initial screening with multiple samples is readily examined. Among the extracts used in the present study, one extract (Citrus unshiu) was found active in this assay system. Furthermore, three representative flavonoids in this active extract of Citrus unshiu peel were tested in MMP-9 reporter system. Nobiletin (NB) of the tested flavonoids suppressed MMP-9 expression without cytotoxicity, which was validated by both real-time polymerase chain reaction (PCR) and zymography analyses. Sustained p38 mitogen activated protein kinase (MAPK) activity, closely associated with induction of MMP-9 under stress condition, was markedly reduced by NB treatment, which implies that modulation of p38MAPK by nobiletin is responsible for reduction of MMP9 expression. Hence, nobiletin, identified from MMP-9 reporter system based screening, may be further applied for the purpose of delaying collagen degradation in skin fibroblasts.Key words Citrus unshiu; nobiletin; flavonoid; matrix metalloprotease 9; p38 mitogen activated protein kinase (MAPK)The integrity of skin connective tissue, which is important for the elasticity of the skin, relies on the levels of dermal extracellular matrix (ECM) proteins, such as collagen type I and III, elastin, and fibronectin. Aging or chronic exposure to ultra violet (UV) causes loss of ECM and the consequent decreased resilience of skin, which are strongly associated with various phenotypes of aged skin (e.g. wrinkle formation). 1)Matrix metalloproteinases (MMPs), members of the zincdependent endoprotease family, serve as important enzyme in degrading dermal ECM.2) Of note, excess expression of MMPs in keratinocytes and dermal fibroblasts, under a variety of stress conditions such as UV radiation (UVR), and heat-shock, 3) which both are closely associated to the aged skin phenotypes, 4,5) contributes to the degradation of ECM proteins, leading to wrinkle formation in photo-aged skin. 6)Therefore, MMPs, induced by a variety of external stresses and capable of degrading collagen and other ECM proteins, have been widely studied as a target for relieving the appearance of aged skin. 7)Among them, gelatinase A (MMP-2) and gelatinase B (MMP-9) were increased by UV radiation in human dermal fibroblasts (hDFs) 8,9) and are responsible for degrading collagens, which are components of the epidermal basement membranes.10) Thereby, the increased activity or expression of gelatinases induced by UV radiation to cause disruption of the basement membrane is considered to be a main cause of skin photoaging, 11,12) which can provide a rationale to target the gelatinases to prevent UV induced wrinkle formation. 7,12) In special, MMP-9 expression is dependent upon activator protei...

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Heat Shock-Induced Matrix Metalloproteinase (MMP)-1 and MMP-3 Are Mediated through ERK and JNK Activation and via an Autocrine Interleukin-6 Loop

Cited by 127 publications

References 47 publications

Cholesterol, a Major Component of Caveolae, Down-regulates Matrix Metalloproteinase-1 Expression through ERK/JNK Pathway in Cultured Human Dermal Fibroblasts

Cholesterol, a Major Component of Caveolae, Down-regulates Matrix Metalloproteinase-1 Expression through ERK/JNK Pathway in Cultured Human Dermal Fibroblasts

Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts

Nobiletin Suppresses MMP-9 Expression through Modulation of p38 MAPK Activity in Human Dermal Fibrobalsts

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