Interleukin (<scp>IL</scp>)‐6 modulates transforming growth factor‐β receptor I and <scp>II</scp> (<scp>TGF</scp>‐β<scp>RI</scp> and <scp>II</scp>) function in epidermal keratinocytes

Luckett-Chastain, Lerin R.; Cottrell, Mackenzie L.; Kawar, Bethany M.; Ihnat, Michael A.; Gallucci, Randle M.

doi:10.1111/exd.13260

Cited by 13 publications

(6 citation statements)

References 51 publications

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“…Indeed, IL-6 also had this capacity, which was an indirect process through coactivating the TGF-β signaling pathway (Luckett-Chastain et al, 2017). Although the IL-6/TGF-β cooperation in the realm of ECM deposition had been documented (Luckett-Chastain et al, 2017;Epstein Shochet et al, 2020), their modulatory link was obscure. Our current study found that IL-6 stimulation induced the overexpression of HDAC6 in HPMCs.…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that IL-6 could trigger the activation of the TGF-β signaling pathway in the fibrosis process (Luckett-Chastain et al, 2017); however, the cross-talk mechanism was obscure. We speculated that IL-6-elicited HDAC6 was required for the activation of the TGF-β signaling pathway, leading to an increased secretion of growth factors, such as CTGF, and the increased expression of transcription factors, such as Snail.…”

Section: Hdac6 Is Required For the Activation Of The Tgf-β Signaling Pathway In Peritoneal Mesothelial Cellsmentioning

confidence: 99%

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Requirement of Histone Deacetylase 6 for Interleukin-6 Induced Epithelial-Mesenchymal Transition, Proliferation, and Migration of Peritoneal Mesothelial Cells

Shi

Tao

et al. 2021

Front. Pharmacol.

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Aims: Influenced by microenvironment, human peritoneal mesothelial cells (HPMCs) acquired fibrotic phenotype, which was identified as the protagonist for peritoneal fibrosis. In this study, we examined the role of histone deacetylase 6 (HDAC6) for interleukin-6 (IL-6) induced epithelial-mesenchymal transition (EMT), proliferation, and migration of HPMCs.Methods: The role of HDAC6 in IL-6-elicited EMT of HPMCs was tested by morphological observation of light microscope, immunoblotting, and immune-fluorescence assay; and the function of HDAC6 in proliferation and migration of HPMCs was examined by CCK-8 assay, wound healing experiment, and immunoblotting.Results: IL-6 stimulation significantly increased the expression of HDAC6. Treatment with tubastatin A (TA), a highly selective HDAC6 inhibitor, or silencing of HDAC6 with siRNA decreased the expression of HDAC6. Moreover, TA or HDAC6 siRNA suppressed IL-6-induced EMT, as evidenced by decreased expressions of α-SMA, Fibronectin, and collagen I and the preserved expression of E-cadherin in cultured HPMCs. Mechanistically, HDAC6 inhibition suppressed the expression of transforming growth factor β (TGFβ) receptor I (TGFβRI), phosphorylation of Smad3, secretion of connective tissue growth factor (CTGF), and transcription factor Snail. On the other hand, the pharmacological inhibition or genetic target of HDAC6 suppressed HPMCs proliferation, as evidenced by the decreased optical density of CCK-8 and the expressions of PCNA and Cyclin E. The migratory rate of HPMCs also decreased. Mechanistically, HDAC6 inhibition blocked the activation of JAK2 and STAT3.Conclusion: Our study illustrated that IL-6-induced HDAC6 not only regulated IL-6 itself downstream JAK2/STAT3 signaling but also co-activated the TGF-β/Smad3 signaling, leading to the change of the phenotype and mobility of HPMCs. HDAC6 could be a potential therapeutic target for the prevention and treatment of peritoneal fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Hdac6 Is Required For the Activation Of The Tgf-β Signaling Pathway In Peritoneal Mesothelial Cellsmentioning

confidence: 99%

Requirement of Histone Deacetylase 6 for Interleukin-6 Induced Epithelial-Mesenchymal Transition, Proliferation, and Migration of Peritoneal Mesothelial Cells

Shi

Tao

et al. 2021

Front. Pharmacol.

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“…158 Interleukin-6 IL-6 is a family of cytokines that have been associated with lung injury and the initiation of lung fibrosis, 159 with fewer fibrotic changes seen in IL-6 deficient mice. 160,161 Animal models show that this cytokine increases the expression of TGF-β receptors and their signal transduction, 162 demonstrating another link between inflammation and fibrosis. IL-6 is essential for host defence against bacterial and viral infections, controlling T cell functions and survival.…”

Section: Cytokinesmentioning

confidence: 99%

Pathological mechanisms and therapeutic outlooks for arthrofibrosis

et al. 2019

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Arthrofibrosis is a fibrotic joint disorder that begins with an inflammatory reaction to insults such as injury, surgery and infection. Excessive extracellular matrix and adhesions contract pouches, bursae and tendons, cause pain and prevent a normal range of joint motion, with devastating consequences for patient quality of life. Arthrofibrosis affects people of all ages, with published rates varying. The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers. However, current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis. The process begins when stress signals stimulate immune cells. The resulting cascade of cytokines and mediators drives fibroblasts to differentiate into myofibroblasts, which secrete fibrillar collagens and transforming growth factor-β (TGF-β). Positive feedback networks then dysregulate processes that normally terminate healing processes. We propose two subtypes of arthrofibrosis occur: active arthrofibrosis and residual arthrofibrosis. In the latter the fibrogenic processes have resolved but the joint remains stiff. The best therapeutic approach for each subtype may differ significantly. Treatment typically involves surgery, however, a pharmacological approach to correct dysregulated cell signalling could be more effective. Recent research shows that myofibroblasts are capable of reversing differentiation, and understanding the mechanisms of pathogenesis and resolution will be essential for the development of cell-based treatments. Therapies with significant promise are currently available, with more in development, including those that inhibit TGF-β signalling and epigenetic modifications. This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments.

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“…The concentrations we have chosen to use, 5-50 ng/mL of IL-6, were according to previous work which shows the biochemical and biological effects of IL-6 in keratinocytes. [45][46][47][48] PHK cells were treated with IL-6 at several different conditions of…”

Section: Treating Phk Cells With Il-6 Does Not Affect Mir-197 Expressionmentioning

confidence: 99%

IL6R is a target of miR‐197 in human keratinocytes

Masalha

Gur‐Wahnon

Meningher

et al. 2020

Experimental Dermatology

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Psoriasis is one of the most common chronic inflammatory skin disorders, with cutaneous and systemic manifestations and substantial negative effects on affected patients' quality of life. [1] MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. [2] Recent studies have revealed that interactions between miRNAs and their targets play critical roles in regulating distinct signalling pathways during skin differentiation. [3,4] Evidence is rapidly accumulating for the roles of miRNAs in the pathogenesis of inflammatory skin disorders. [5][6][7] In previous studies, others and we have shown that miR-197-3p (hereafter named miR-197) expression is downregulated in the psoriatic lesions compared to normal or uninvolved psoriatic skin. [6,8] Moreover, we showed that miR-197 modulates IL-22 and IL-17 signalling in normal keratinocytes (KC). Specifically, we found that both IL-22 and IL-17 activated the transcription of miR-197, and miR-197 targets and inhibits the expression of both the IL22RA1 subunit of

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Interleukin (IL)‐6 modulates transforming growth factor‐β receptor I and II (TGF‐βRI and II) function in epidermal keratinocytes

Cited by 13 publications

References 51 publications

Requirement of Histone Deacetylase 6 for Interleukin-6 Induced Epithelial-Mesenchymal Transition, Proliferation, and Migration of Peritoneal Mesothelial Cells

Requirement of Histone Deacetylase 6 for Interleukin-6 Induced Epithelial-Mesenchymal Transition, Proliferation, and Migration of Peritoneal Mesothelial Cells

Pathological mechanisms and therapeutic outlooks for arthrofibrosis

IL6R is a target of miR‐197 in human keratinocytes

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