Stat3

Prêle, Cecilia M.; Yao, Eric; O’Donoghue, Robert J.J.; Mutsaers, Steven E.; Knight, Darryl A.

doi:10.1513/pats.201201-007aw

Cited by 51 publications

(17 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL-6 signaling phosphorylates and activates STAT3, a transcription factor important in the pathogenesis of liver, skin and kidney fibrosis (67, 68). Increased STAT3 activation has been reported in IPF (47, 69).…”

Section: Resultsmentioning

confidence: 99%

Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis

Le¹,

Karmouty‐Quintana

Melicoff

et al. 2014

The Journal of Immunology

263

192

View full text Add to dashboard Cite

Idiopathic Pulmonary Fibrosis (IPF) is a lethal lung disease with progressive fibrosis and death within 2–3 years of diagnosis. IPF incidence and prevalence rates are increasing annually with few effective treatments available. Inhibition of interleukin 6 (IL-6) results in the attenuation of pulmonary fibrosis in mice. It is unclear whether this is due to blockade of classical signaling, mediated by membrane-bound IL-6 receptor alpha (mIL-6Rα), or trans signaling, mediated by soluble IL-6Rα (sIL-6Rα). Our study assessed the role of sL-6Rα in IPF. We demonstrated elevations of sIL-6Rα in IPF patients and in mice during the onset and progression of fibrosis. We demonstrated that protease-mediated cleavage from lung macrophages was important in production of sL-6Rα. In vivo neutralization of sIL-6Rα attenuated pulmonary fibrosis in mice as seen by reductions in myofibroblasts, fibronectin and collagen in the lung. In vitro activation of IL-6 trans signaling enhanced fibroblast proliferation and extracellular matrix protein production, effects relevant in the progression of pulmonary fibrosis. Together these findings demonstrate that the production of sL-6Rα from macrophages in the diseased lung contributes to IL-6 trans signaling that in turn influences events crucial in pulmonary fibrosis.

show abstract

Section: Resultsmentioning

confidence: 99%

Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis

Le¹,

Karmouty‐Quintana

Melicoff

et al. 2014

The Journal of Immunology

263

192

View full text Add to dashboard Cite

show abstract

“…Previous studies in our lung transplant models demonstrated that cJun activation by hypoxia inducble factor (HIF1α) potentially induced VEGF upegulation with potential fibrotic effect (Tiriveedhi et al, 2012a). Prele et al have demonstrated that STAT-3 is the key central factor in inducing idiopathic pulmonary disease, a fibrotic lung disease (Prele et al, 2012). Transcription factor STAT-3 is involved in JAK/STAT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect of pro-inflammatory TNFα and IL-17 in periostin mediated collagen deposition: Potential role in liver fibrosis

Amara

López

Banan

et al. 2015

Molecular Immunology

View full text Add to dashboard Cite

Background The pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, and interleukin (IL)-17, have been implicated in the pathogenesis of liver fibrosis. In this study, we investigated the role of TNFα and IL-17 towards induction of profibrotic factor, periostin. Methods HepG2 cells were cultured and treated with inflammatory cytokines, TNFα and IL-17. Computational promoter sequence analysis of the periostin promoter was performed to define the putative binding sites for transcription factors. Transcription factors were analyzed by Western blot and Chromatin Immunoprecipitation. Periostin and transcription factor expression analysis was performed by RT-PCR, Western blot, and fluorescence microscopy. Type I collagen expression from fibroblast cultures was analyzed by Western blot and Sircol soluble collagen assay. Results Activation of HepG2 Cells with TNFα and IL-17 enhanced the expression of periostin (3.5 and 4.4 fold, respectively p<0.05) compared to untreated cells. However, combined treatment with both TNFα and IL-17 at similar concentration demonstrated a 13.3 fold increase in periostin (p<0.01), thus suggesting a synergistic role of these cytokines. Periostin promoter analysis and specific siRNA knock-down revealed that TNFα induces periostin through cJun, while IL-17 induced periostin via STAT-3 signaling mechanisms. Treatment of the supernatant from the cytokine activated HepG2 cells on fibroblast cultures induced enhanced expression of type I collagen (>9.1 fold, p<0.01), indicative of a direct fibrogenic effect of TNFα and IL-17. Conclusion TNFα and IL-17 induced fibrogenesis through cJun and STAT-3 mediated expression of profibrotic biomarker, periostin. Therefore, periostin might serve as a novel biomarker in early diagnosis of liver fibrosis.

show abstract

“…In human lung fibroblasts, SRF expression is dramatically increased following exposure to TGFβ [33] thus this is a likely mechanism for the TGFβ1-induced increase in GSTCD and INTS12 mRNA in airway smooth muscle cells. STAT3 has recently been suggested to be a central mediator of pulmonary fibrosis via dysregulation of epithelial-mesenchymal communication [34]. GR-mediated signalling occurs via both gene repression and activation and it is unclear which contributes to the anti-inflammatory effects of glucocorticoids.…”

Section: Discussionmentioning

confidence: 99%

GSTCD and INTS12 Regulation and Expression in the Human Lung

et al. 2013

View full text Add to dashboard Cite

Genome-Wide Association Study (GWAS) meta-analyses have identified a strong association signal for lung function, which maps to a region on 4q24 containing two oppositely transcribed genes: glutathione S-transferase, C-terminal domain containing (GSTCD) and integrator complex subunit 12 (INTS12). Both genes were found to be expressed in a range of human airway cell types. The promoter regions and transcription start sites were determined in mRNA from human lung and a novel splice variant was identified for each gene. We obtained the following evidence for GSTCD and INTS12 co-regulation and expression: (i) correlated mRNA expression was observed both via Q-PCR and in a lung expression quantitative trait loci (eQTL) study, (ii) induction of both GSTCD and INTS12 mRNA expression in human airway smooth muscle cells was seen in response to TGFβ1, (iii) a lung eQTL study revealed that both GSTCD and INTS12 mRNA levels positively correlate with percent predicted FEV1, and (iv) FEV1 GWAS associated SNPs in 4q24 were found to act as an eQTL for INTS12 in a number of tissues. In fixed sections of human lung tissue, GSTCD protein expression was ubiquitous, whereas INTS12 expression was predominantly in epithelial cells and pneumocytes. During human fetal lung development, GSTCD protein expression was observed to be highest at the earlier pseudoglandular stage (10-12 weeks) compared with the later canalicular stage (17-19 weeks), whereas INTS12 expression levels did not alter throughout these stages. Knowledge of the transcriptional and translational regulation and expression of GSTCD and INTS12 provides important insights into the potential role of these genes in determining lung function. Future work is warranted to fully define the functions of INTS12 and GSTCD.

show abstract

Stat3

Cited by 51 publications

References 83 publications

Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis

Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis

Synergistic effect of pro-inflammatory TNFα and IL-17 in periostin mediated collagen deposition: Potential role in liver fibrosis

GSTCD and INTS12 Regulation and Expression in the Human Lung

Contact Info

Product

Resources

About