Role of p38 MAPK in Transforming Growth Factor β Stimulation of Collagen Production by Scleroderma and Healthy Dermal Fibroblasts

Sato, Madoka; Shegogue, Daniel; Gore, E.A.; Smith, Edwin A.; McDermott, Paul J.; Trojanowska, Maria

doi:10.1046/j.1523-1747.2002.01719.x

Cited by 105 publications

(82 citation statements)

References 42 publications

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“…In addition, p38 phosphorylation is required for TGF-β-induced collagen production by fibroblasts [45]. These results suggest that p38 signalling may be important for the development of interstitial fibrosis in diabetic kidneys.…”

Section: Discussionmentioning

confidence: 74%

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

et al. 2004

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Aims/hypothesis. Inflammation and fibrosis are pathological mechanisms that are partially regulated by cell signalling through the p38 mitogen-activated protein kinase (MAPK) pathway. Elements of the diabetic milieu such as high glucose and advanced glycation endproducts induce activation of this pathway in renal cells. Therefore, we examined whether p38 MAPK signalling is associated with the development of human and experimental diabetic nephropathy. Methods. Immunostaining identified phosphorylated (active) p38 MAPK in human biopsies with no abnormality (n=6) and with Type 2 diabetic nephropathy (n=12). Changes in kidney levels of phosphorylated p38 were assessed by immunostaining and western blotting in mice with streptozotocin-induced Type 1 diabetes that had been killed after 0.5, 2, 3, 4 and 8 months, and in Type 2 diabetic db/db mice at 2, 4, 6 and 8 months of age. Results. Phosphorylated p38 was detected in some intrinsic cells in normal human kidney, including podocytes, cortical tubules and occasional interstitial cells. Greater numbers of these phosphorylated p38+ cells were observed in diabetic patients, and phosphorylated p38 was identified in accumulating interstitial macrophages and myofibroblasts. A similar pattern of p38 activation was observed in both mouse models of diabetes. In mice, kidney levels of phosphorylated p38 increased (2-6 fold) following the onset of Type 1 and Type 2 diabetes. In both mouse models, interstitial phosphorylated p38+ cells were associated with hyperglycaemia, increased HbA 1 c levels and albuminuria. Further assessment of streptozotocin-induced diabetic nephropathy showed that interstitial phosphorylated p38+ cells correlated with interstitial fibrosis (myofibroblasts, collagen). Conclusions/interpretation. Increased p38 MAPK signalling is a feature of human and experimental diabetic nephropathy. Time course studies in mouse models suggest that phosphorylation of p38 plays a pathological role, particularly in the development of interstitial fibrosis.

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Section: Discussionmentioning

confidence: 74%

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

et al. 2004

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“…p38MAPK has also been shown to be required for TGF-b-dependent stimulation of matrix production in dermal fibroblasts, and thus inhibition of p38MAPK could potentially be effective in preventing dermal scarring. 24,26,30 It has also been shown that p38MAPK-dependent activation of Smad3 promoted deposition of extracellular matrix by myofibroblasts both in vitro and in vivo. 24,26,30,31 These reports together with our findings lead us to hypothesize that inhibition of p38MAPK may be beneficial in preventing/treating PVR.…”

Section: Discussionmentioning

confidence: 99%

“…24,26,30 It has also been shown that p38MAPK-dependent activation of Smad3 promoted deposition of extracellular matrix by myofibroblasts both in vitro and in vivo. 24,26,30,31 These reports together with our findings lead us to hypothesize that inhibition of p38MAPK may be beneficial in preventing/treating PVR. Although PVR is caused by the activation of many cell types, that is, retinal glial components, vascular cells, and so on, activation and fibroblastic transformation of RPE cells is a critical feature in the development of this disease.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells

Saika

Yamanaka

Ikeda

et al. 2005

Laboratory Investigation

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Proliferative vitreoretinopathy (PVR) is one of the major causes of the failure of retinal detachment surgery. Its pathogenesis includes a fibrotic reaction by the retinal pigment epithelium and other retina-derived non-neural cells, leading to fixation of the detached retina. We examined the role of p38 mitogen-activated protein kinase (MAPK) in transforming growth factor (TGF)-b2-dependent enhancement of the fibrogenic reaction in a human retinal pigment epithelial cell line, ARPE-19, and also evaluated the therapeutic efficacy of inhibiting p38MAPK by adenoviral gene transfer of dominant-negative (DN) p38MAPK in a mouse model of PVR. Exogenous TGF-b2 activates p38MAPK in ARPE-19 cells. It also suppresses cell proliferation, but this was unaffected by addition of the p38MAPK inhibitor, SB202190. SB202190 interfered with TGF-b2-dependent cell migration and production of collagen type I and fibronectin, but had no effect on basal levels of these activities. While SB202190 did not affect phosphorylation of the C-terminus of Smads2/3, it did suppress the transcriptional activity of Smads3/4 as indicated by a reporter gene, CAGA12-Luc. Gene transfer of DN-p38MAPK attenuated the post-retinal detachment fibrotic reaction of the retinal pigment epithelium in vivo in mice, supporting its effectiveness in preventing/treating PVR. Laboratory Investigation (2005) 85, 838-850.

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“…It is well established that collagen protein degradation, mRNA stability, and transcription are tightly regulated during collagen biosynthesis. Signals from external stimuli such as cytokines (1)(2)(3), nutrients (4), and cell interactions (5, 6) modulate these processes via several pathways, including TGF-␤ 1 / p38 (7,8), PKC (9), and stress-activated protein kinase/c-Jun N-terminal kinase (10,11). Despite these advances, the pathways controlling collagen biosynthesis are not fully characterized, prompting us to further examine potential signaling molecules involved in type I collagen regulation.…”

mentioning

confidence: 99%

Mammalian Target of Rapamycin Positively Regulates Collagen Type I Production via a Phosphatidylinositol 3-Kinase-independent Pathway

Shegogue¹,

Trojanowska

2004

Journal of Biological Chemistry

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117

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The mammalian target of rapamycin (mTOR) is a multifunctional protein involved in the regulation of cell growth, proliferation, and differentiation. The goal of this study was to determine the role of mTOR in type I collagen regulation. The pharmacological inhibitor of phosphatidylinositol (PI) 3-kinase, LY294002, significantly inhibited collagen type I protein and mRNA levels. The effects of LY294002 were more pronounced on the collagen ␣1(I) chain, which was inhibited at the transcriptional and mRNA stability levels versus collagen ␣2(I) chain, which was inhibited through a decrease in mRNA stability. In contrast, addition of the PI 3-kinase inhibitor, wortmannin, did not alter type I collagen steady-state mRNA levels. This observation and further experiments using an inactive LY294002 analogue suggested that collagen mRNA levels are inhibited independent of PI 3-kinase. Additional experiments have established that mTOR positively regulates collagen type I synthesis in human fibroblasts. These conclusions are based on results demonstrating that inhibition of mTOR activity using a specific inhibitor, rapamycin, reduced collagen mRNA levels. Furthermore, decreasing mTOR expression by about 50% by using small interfering RNA resulted in a significant decrease of collagen mRNA (75% COL1A1 decrease and 28% COL1A2 decrease) and protein levels. Thus, mTOR plays an essential role in regulating basal expression of collagen type I gene in dermal fibroblasts. Together, our data suggest that the classical PI 3-kinase pathway, which places mTOR downstream of PI 3-kinase, is not involved in mTOR-dependent regulation of type I collagen synthesis in dermal fibroblasts. Because collagen overproduction is a main feature of fibrosis, identification of mTOR as a critical mediator of its regulation may provide a suitable target for drug or gene therapy.A common characteristic of all fibrotic diseases, including scleroderma, is an abnormal accumulation of extracellular matrix proteins. Fibrotic lesions disrupt normal tissue architecture and contribute to organ failure. Type I collagen, the primary component of fibrotic lesions, is a triple helix composed of two ␣1 chains and one ␣2 chain. These chains, although coordinately expressed, are not regulated via the same mechanisms. It is well established that collagen protein degradation, mRNA stability, and transcription are tightly regulated during collagen biosynthesis. Signals from external stimuli such as cytokines (1-3), nutrients (4), and cell interactions (5, 6) modulate these processes via several pathways, including TGF-␤ 1 / p38 (7, 8), PKC (9), and stress-activated protein kinase/c-Jun N-terminal kinase (10, 11). Despite these advances, the pathways controlling collagen biosynthesis are not fully characterized, prompting us to further examine potential signaling molecules involved in type I collagen regulation.Prior studies suggested the involvement of phosphatidylinositol 3-kinase (PI 3-kinase), a ubiquitous lipid kinase, in collagen regulation. For example, Ivarsson et al....

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Role of p38 MAPK in Transforming Growth Factor β Stimulation of Collagen Production by Scleroderma and Healthy Dermal Fibroblasts

Cited by 105 publications

References 42 publications

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy

Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells

Mammalian Target of Rapamycin Positively Regulates Collagen Type I Production via a Phosphatidylinositol 3-Kinase-independent Pathway

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