ArticleJournal of biomedical science2018
MEKK1, JNK, and SMAD3 mediate CXCL12-stimulated connective tissue growth factor expression in human lung fibroblasts.
Article in Journal of biomedical science, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 27 citations in OpenAlex.
- Paraxanthine and azilsartan attenuate gentamicin-induced renal fibrosis via modulation of TGF-β1/Smad3/7 signaling and miRNA-21/miRNA-200b expression.Journal of translational medicine · 2026Article
- Cellular senescence in Crohn's disease: a double-edged sword in intestinal fibrosis.Frontiers in immunology · 2026Review
- The CXCL12/CXCR4 Axis in Sepsis-Induced Acute Lung Injury: Mechanisms and Therapeutic Potential.Current issues in molecular biology · 2025Review
- Advances in JNK inhibitor development: therapeutic prospects in neurodegenerative diseases and fibrosis.Archives of pharmacal research · 2025Review
- The role of JNK signaling pathway in organ fibrosis.Journal of advanced research · 2025Review
- Chemokines as key mediators in RIPI: pathophysiology and translational potential.Frontiers in immunology · 2025Review
- Review
- Platelet-Rich Fibrin Increases CXCL8 Expression in Gingival Fibroblasts.Biomedicines · 2024Article
- Connective tissue growth factor: Role in trabecular meshwork remodeling and intraocular pressure lowering.Experimental biology and medicine (Maywood, N.J.) · 2023Review
- Endothelin-1 induces connective tissue growth factor expression in human lung fibroblasts by disrupting HDAC2/Sin3A/MeCP2 corepressor complex.Journal of biomedical science · 2023Article
- Specific epigenetic regulators serve as potential therapeutic targets in idiopathic pulmonary fibrosis.Heliyon · 2022Review
- Endoplasmic Reticulum Stress Induces CAP2 Expression Promoting Epithelial-Mesenchymal Transition in Liver Cancer Cells.Molecules and cells · 2021Article
- Protective effects of Astragaloside IV against oxidative injury and apoptosis in cultured astrocytes by regulating Nrf2/JNK signaling.Experimental brain research · 2021Article
- Idiopathic Pulmonary Fibrosis: An Update on Pathogenesis.Frontiers in pharmacology · 2021Review
- Pulmonary toxicants and fibrosis: innate and adaptive immune mechanisms.Toxicology and applied pharmacology · 2020Review
- Abundance of Non-Polarized Lung Macrophages with Poor Phagocytic Function in Chronic Obstructive Pulmonary Disease (COPD).Biomedicines · 2020Article
- Baicalin alleviates bleomycin‑induced pulmonary fibrosis and fibroblast proliferation in rats via the PI3K/AKT signaling pathway.Molecular medicine reports · 2020Article
- Role of the CXCR4/ALK5/Smad3 Signaling Pathway in Cancer-Induced Bone Pain.Journal of pain research · 2020Article
- CXCR4 knockdown prevents inflammatory cytokine expression in macrophages by suppressing activation of MAPK and NF-κB signaling pathways.Cell & bioscience · 2019Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundIn idiopathic pulmonary fibrosis, the interaction of CXCL12 and CXC receptor 4 (CXCR4) plays a critical role in lung fibrosis. Connective tissue growth factor (CTGF) overexpression underlies the development of pulmonary fibrosis. Our previous report showed that the Rac1-dependent extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and activator protein (AP)-1 pathways are involved in CXCL12-generated CTGF expression in human lung fibroblasts (WI-38). In present study, we additionally inspected the involvement of mitogen-activated protein kinase kinase kinase 1 (MEKK1)/JNK-dependent SMAD3 in CXCL12-triggered CTGF expression in WI-38 cells.
methodsWI-38 cells were stimulated with CXCL12 in the absence or presence of specific inhibitors or small interfering RNAs (siRNAs). CTGF expression and signaling transduction molecules were assessed by Western blot, luciferase activity assay, or ChIP assay.
resultsCXCL-12-induced CTGF expression was attenuated by SIS3 (a SMAD3 inhibitor) and SMAD3 siRNA, but not by SB431542 (an activin receptor-like kinase 5, ALK5, inhibitor). CXCL12-stimulated CTGF expression was also attenuated by MEKK1 siRNA. Treatment of cells with CXCL12 caused an increase in SMAD3 phosphorylation at Ser208, translocation to nuclei, SMAD3-luciferase activity, and recruitment of SMAD3 to the CTGF promoter. Stimulation of cells with CXCL12 resulted in increase in JNK phosphorylation at Thr183/Tyr185 and MEKK1 phosphorylation at Thr261. Moreover, CXCL12-mediated SMAD3 phosphorylation or SMAD3-luciferase activity was inhibited by MEKK1 siRNA or SP600125. Finally, CXCL12-mediated JNK phosphorylation was attenuated by MEKK1 siRNA.
conclusionIn conclusion, results of this study suggest that CXCL12 activates the MEKK1/JNK signaling pathway, which in turn initiates SMAD3 phosphorylation, its translocation to nuclei, and recruitment of SMAD3 to the CTGF promoter, which ultimately induces CTGF expression in human lung fibroblasts.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.