C-Jun-NH<sub>2</sub>-Terminal Kinase Mediates Expression of Connective Tissue Growth Factor Induced by Transforming Growth Factor-β1 in Human Lung Fibroblasts

Utsugi, Mitsuyoshi; Dobashi, Kunio; Ishizuka, Tamotsu; Masubuchi, Ken; Shimizu, Yasuo; Nakazawa, Takahiro; Mori, Masatomo

doi:10.1165/rcmb.4892

Cited by 80 publications

(78 citation statements)

References 39 publications

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“…Thus, the increased Smad2 activity and decreased c-Jun activity caused by JNK inhibition plays an agonistic role in TGF-␤ induction of CTGF expression in embryonic lung explants. This is different from what has been reported in mature lung fibroblasts (40).…”

Section: Discussioncontrasting

confidence: 99%

“…This involves c-Jun binding to Smad2/3, blocking its interaction with the Smad element of the CTGF promoter (39). However, studies have also demonstrated that TGF-␤ activation of Smad2 and induction of CTGF in human lung fibroblasts is attenuated by JNK inhibition (40). Our previous studies have demonstrated that induction of CTGF expression by TGF-␤1 in embryonic lung explants is Smad-dependent (22).…”

Section: Discussionmentioning

confidence: 94%

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Inhibition of JNK Enhances TGF-β1-Activated Smad2 Signaling in Mouse Embryonic Lung

Kasisomayajula

Peng

et al. 2009

Pediatr Res

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The Smad2/3 pathway plays a key role in mediating TGF-␤1 inhibition of branching morphogenesis and induction of connective tissue growth factor (CTGF) expression in embryonic lungs. Because a number of cell-specific interactions have been described between TGF-␤1-driven Smad signaling and the c-Jun N-terminal kinase (JNK) pathway, we have investigated the effects of JNK inhibition on TGF-␤1 activation of Smad2, inhibition of branching, induction of CTGF expression, and apoptosis in mouse embryonic lung explants. Mouse embryonic day 12.5 (E12.5) lung explants were treated with TGF-␤1 in the presence or absence of a specific pharmacologic JNK inhibitor (SP600125) and a specific JNK peptide inhibitor (JNKI). We found that TGF-␤1 activated the JNK pathway by stimulating c-Jun phosphorylation, which was blocked by JNK inhibitors. Treatment with SP600125 stimulated Smad2 phosphorylation and enhanced TGF-␤1-induced Smad2 phosphorylation. Treatment with JNK inhibitors also decreased normal branching morphogenesis and induced CTGF expression as well as augmented TGF-␤1 inhibition of branching and induction of CTGF expression. Furthermore, JNK inhibition-induced apoptosis. Our results demonstrate that inhibition of the JNK pathway promotes TGF-␤1-driven Smad2 responses in lung branching morphogenesis. These data suggest that the JNK pathway may antagonize TGF-␤1 dependent Smad2 signaling during mouse embryonic lung development.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 94%

Inhibition of JNK Enhances TGF-β1-Activated Smad2 Signaling in Mouse Embryonic Lung

Kasisomayajula

Peng

et al. 2009

Pediatr Res

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“…This probably reflects an indirect effect of the reduction in TGF-␤1 mRNA levels. However, CC-401 may have inhibited the CTGF response in a direct manner because TGF-␤1-induced CTGF production in human lung fibroblasts is JNK dependent (19). The reduction in ␣-SMA ϩ myofibroblast accumulation that was seen with CC-401 treatment in the UUO model could operate via indirect or direct mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro studies suggest a role for JNK signaling in TGF-␤1 induced fibronectin production in fibro-blasts and in TGF-␤1 induced connective tissue growth factor (CTGF) production (18,19). However, a role for JNK signaling in tissue fibrosis has yet to be demonstrated clearly.…”

mentioning

confidence: 99%

A Pathogenic Role for c-Jun Amino-Terminal Kinase Signaling in Renal Fibrosis and Tubular Cell Apoptosis

Ma¹,

Flanc²,

Tesch³

et al. 2007

Journal of the American Society of Nephrology

152

139

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Renal fibrosis and tubular apoptosis are common mechanisms of progressive kidney disease. In vitro studies have implicated the c-Jun amino-terminal kinase (JNK) pathway in these processes. Both of the major JNK isoforms, JNK1 and JNK2, are expressed in the kidney, but their relative contribution to JNK signaling is unknown. This study investigated the role of JNK signaling in renal fibrosis and tubular apoptosis in the unilateral ureteral obstruction model using two different approaches: (1) Mice that were deficient in either JNK1 or JNK2 and (2) a specific inhibitor of all JNK isoforms, CC-401. Western blotting and immunostaining identified a marked increase in JNK signaling in the obstructed kidney, with substantial redundancy between JNK1 and JNK2 isoforms. Administration of CC-401 blocked JNK signaling in the rat obstructed kidney and significantly inhibited renal fibrosis in terms of interstitial myofibroblast accumulation and collagen IV deposition. This effect was attributed to suppression of gene transcription for the profibrotic molecules TGF-␤1 and connective tissue growth factor. CC-401 treatment also significantly reduced tubular apoptosis in the obstructed kidney. Genetic deletion of JNK1 or JNK2 did not protect mice from renal fibrosis in the unilateral ureteral obstruction model, but JNK1 deletion did result in a significant reduction in tubular cell apoptosis. In conclusion, this is the first study to demonstrate that JNK signaling plays a pathogenic role in renal fibrosis and tubular apoptosis. Furthermore, JNK1 plays a nonredundant role in tubular cell apoptosis. These studies identify the JNK pathway as a potential therapeutic target in progressive kidney disease.

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“…ERK1/2 32-34 and JNK [35][36][37][38] are involved in fibrotic changes such as collagen synthesis and the induction of TGF-␤ and CTGF expression. To clarify the effect of ERK1/2 and JNK inhibition on the progression of fibrosis, we administered PD98059 and SP600125 in bleomycininduced fibrosis.…”

Section: Discussionmentioning

confidence: 99%

α2-Antiplasmin Is Associated with the Progression of Fibrosis

Kanno

Kawashita

Minamida

et al. 2010

The American Journal of Pathology

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Systemic sclerosis results in tissue fibrosis due to the activation of fibroblasts and the ensuing overproduction of the extracellular matrix. We previously reported that the absence of ␣2-antiplasmin (␣2AP) attenuated the process of dermal fibrosis; however, the detailed mechanism of how ␣2AP affects the progression of fibrosis remained unclear. The goal of the present study was to examine the role of ␣2AP in fibrotic change. We observed significantly higher levels of ␣2AP expression in the skin of bleomycininjected systemic sclerosis model mice in comparison with the levels seen in control mice. We also demonstrated that ␣2AP induced myofibroblast differentiation , and the absence of ␣2AP attenuated the induction of myofibroblast differentiation. Moreover, we found that connective tissue growth factor induced the expression of ␣2AP through both the extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways in fibroblasts. Interestingly , ␣2AP also induced transforming growth factor-␤ expression through the same pathways, and the inhibition of ERK1/2 and JNK slowed the progression of bleomycin-induced fibrosis. Our findings suggest that ␣2AP is associated with the progression of fibrosis , and regulation of ␣2AP expression by the ERK1/2 and JNK pathways may be an effective antifibrotic therapy for the treatment of systemic sclerosis.

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C-Jun-NH₂-Terminal Kinase Mediates Expression of Connective Tissue Growth Factor Induced by Transforming Growth Factor-β1 in Human Lung Fibroblasts

Cited by 80 publications

References 39 publications

Inhibition of JNK Enhances TGF-β1-Activated Smad2 Signaling in Mouse Embryonic Lung

Inhibition of JNK Enhances TGF-β1-Activated Smad2 Signaling in Mouse Embryonic Lung

A Pathogenic Role for c-Jun Amino-Terminal Kinase Signaling in Renal Fibrosis and Tubular Cell Apoptosis

α2-Antiplasmin Is Associated with the Progression of Fibrosis

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C-Jun-NH2-Terminal Kinase Mediates Expression of Connective Tissue Growth Factor Induced by Transforming Growth Factor-β1 in Human Lung Fibroblasts

Cited by 80 publications

References 39 publications

Inhibition of JNK Enhances TGF-β1-Activated Smad2 Signaling in Mouse Embryonic Lung

Inhibition of JNK Enhances TGF-β1-Activated Smad2 Signaling in Mouse Embryonic Lung

A Pathogenic Role for c-Jun Amino-Terminal Kinase Signaling in Renal Fibrosis and Tubular Cell Apoptosis

α2-Antiplasmin Is Associated with the Progression of Fibrosis

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C-Jun-NH₂-Terminal Kinase Mediates Expression of Connective Tissue Growth Factor Induced by Transforming Growth Factor-β1 in Human Lung Fibroblasts