Conversion of a high molecular weight latent β-TGF from chicken embryo fibroblasts into a low molecular weight active β-TGF under acidic conditions

Lawrence, David A.; Pircher, Renée; Jullien, P.

doi:10.1016/0006-291x(85)91239-2

Cited by 344 publications

(169 citation statements)

References 6 publications

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“…Our data show that EGF strongly potentiated anchorageindependent growth caused by the medium conditioned by RA-treated PC12 cells, which suggests that the factors released could belong to the TGF-b family. The ®nding that colony formation also signi®cantly increased after acidi®cation of the media further con®rms TGF-b secretion, since the factors belonging to this family are released by the cells in a latent, inactive form, which can be activated`in vitro' by acidi®cation (Lawrence et al, 1985). Our data also show that the non-activated medium conditioned by RA-treated PC12 cells produces some anchorage-independent NRK growth.…”

Section: Discussionsupporting

confidence: 76%

Retinoic acid induces secretion of transforming growth factors by PC12 pheochromocytoma cells

1997

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Section: Discussionsupporting

confidence: 76%

Retinoic acid induces secretion of transforming growth factors by PC12 pheochromocytoma cells

1997

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“…2E). Some physical conditions (e.g., heat and pH extremes) have been shown to denature LAP and release active TGFb1 (29). Interestingly, when the culture supernatant was acidtreated for 10 min and then the pH neutralized, the model produced significantly more total TGFb1 (i.e., both active and latent forms) in KC(+) cultures than in KC(−) cultures (Fig.…”

Section: Endogenous Latent Tgf-b1 Is Involved In the Differentiation mentioning

confidence: 92%

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

et al. 2014

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Abstract. Transforming growth factorb1 (TGFb1) reportedly causes the differentiation of fibroblasts to myofibroblasts during wound healing. We investigated the mechanism underlying the activation of latent TGFb1 released by keratinocytes in efforts to identify promising pharma cological approaches for the prevention of hypertrophic scar formation. A threedimensional col lagen gel matrix culture was prepared using rat keratinocytes and dermal fibroblasts. Stratified keratinocytes promoted the TGF receptor-dependent increase in asmooth muscle actin (aSMA) immunostaining and mRNA levels in fibroblasts. Latent TGFb1 was found to be localized suprabasally and secreted. aSMA expression was inhibited by an antia v integrin antibody and a matrix metalloproteinase (MMP) inhibitor, GM6001. In a twodimensional fibroblast culture, aSMA expression depended on the production of endogenous TGFb1 and required a v integrin or MMP for the response to recombinant latent TGFb1. In keratinocyteconditioned medium, MMPdependent latent TGFb1 secretion was detected. Applying this medium to the fibroblast culture enhanced aSMA production. This effect was decreased by GM6001, the antia v integrin antibody, or the preabsorption of latent TGFb1. These results indicate that keratinocytes secrete latent TGFb1, which is liberated to fibroblasts over distance and is activated to produce aSMA with the aid of a positivefeedback loop. MMP inhibition was effective for targeting both keratinocytes and fibroblasts in this model. [Supplementary Figure: available only at http://dx

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“…In vitro activation of TGF-b is often accomplished at extremes of pH (10). The role of endogenous more physiological pH changes pertaining to TGF-b activation is not well understood.…”

mentioning

confidence: 99%

Lactic Acid Is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation via pH-Dependent Activation of Transforming Growth Factor-β

Kottmann¹,

Kulkarni²,

Smolnycki³

et al. 2012

Am J Respir Crit Care Med

292

279

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Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. Objectives: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. Methods: We used metabolomic analysis to examine cellular metabolism in lung tissue from patients with IPF and determined the effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-b activation in vitro. Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; a-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a (HIF1a). Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low-dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b-induced myofibroblast differentiation. Conclusions: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pHdependent activation of TGF-b. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.

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Conversion of a high molecular weight latent β-TGF from chicken embryo fibroblasts into a low molecular weight active β-TGF under acidic conditions

Cited by 344 publications

References 6 publications

Retinoic acid induces secretion of transforming growth factors by PC12 pheochromocytoma cells

Retinoic acid induces secretion of transforming growth factors by PC12 pheochromocytoma cells

Proteolytic and Non-proteolytic Activation of Keratinocyte-Derived Latent TGF-β1 Induces Fibroblast Differentiation in a Wound-Healing Model Using Rat Skin

Lactic Acid Is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation via pH-Dependent Activation of Transforming Growth Factor-β

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