Potential roles of the IL-6 family in conjunctival fibrosis

Watanabe-Kitamura, Fumika; Ogawa, Akiko; Fujimoto, Tomokazu; Iraha, Satoshi; Inoue-Mochita, Miyuki; Watanabe, Tetsu; Takahashi, Eri; Tanihara, Hidenobu; Inoue, Toshihiro

doi:10.1016/j.exer.2021.108708

Cited by 7 publications

(7 citation statements)

References 28 publications

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“…4 ). Furthermore, our immunohistochemistry (IHC) assay showed increased expression of the collagen-1, Smad2, transforming growth factor-β1 (TGF-β1), and interleukin-6 (IL-6), which are known fibrosis biomarkers ( 33 – 37 ) ( Fig. 5A ).…”

Section: Resultsmentioning

confidence: 96%

Mycobiome Dysbiosis in Women with Intrauterine Adhesions

et al. 2022

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Section: Resultsmentioning

confidence: 96%

Mycobiome Dysbiosis in Women with Intrauterine Adhesions

et al. 2022

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“…[37][38][39] A striking finding was the expression of markers associated with fibrosis and remodeling such as TNFSF14 (LIGHT), CXCL-1, CXCL-5, TGFβ, IL-13, IL-6, OSM, MMP-1, and LIF in DAOSD tear fluids. [40][41][42] TNFSF14 is an important cytokine orchestrating inflammation and remodeling as it regulates the infiltration, survival, and cytokine production of T cells, macrophages and eosinophils, as well as the proliferation of structural cells and their expression of chemokines, growth factors, and metalloproteinases. 40 IL-7 was the only differentially expressed marker found upregulated in tear fluids taken from non-AD patients under dupilumab therapy.…”

Section: Il-12b (C)mentioning

confidence: 99%

Dupilumab‐associated ocular surface disease is characterized by a shift from Th2/Th17 toward Th1/Th17 inflammation

Thormann,

Lüthi,

Deniau

et al. 2024

Allergy

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BackgroundDupilumab is used for the treatment of atopic dermatitis (AD). Approximately one third of AD patients develop a dupilumab‐associated ocular surface disease (DAOSD), of which the pathomechanism is poorly understood. This study aimed at investigating inflammatory markers in tear fluids of patients on dupilumab therapy.MethodsTear fluids were collected from AD patients with DAOSD (ADwDAOSD), AD patients without DAOSD (ADw/oDAOSD), and non‐AD patients before and during dupilumab therapy, and analyzed using a specialized proteomic approach quantifying inflammatory markers. The ocular surface microbiome was determined by next generation sequencing technology.ResultsUpon dupilumab therapy, an upregulation of 31 inflammatory markers was observed in DAOSD tear fluids compared to baseline in AD patients. While IL‐12B was upregulated in both ADwDAOSD and ADw/oDAOSD groups, the pattern of inflammatory markers significantly differed between groups and over time. In the ADwDAOSD group, a shift from a mixed Th2/Th17 pattern at baseline toward a Th1/Th17 profile under dupilumab was observed. Furthermore, an upregulation of remodeling and fibrosis markers was seen in DAOSD. Semantic map and hierarchical cluster analyses of baseline marker expression revealed four clusters distinguishing between AD and non‐AD as well as ADwDAOSD and ADw/oDAOSD patient groups. In a pilot study, dupilumab therapy was associated with a decrease in richness of the ocular surface microbiome.ConclusionsDAOSD is characterized by a Th1/Th17 cytokine profile and an upregulation of markers known to promote remodeling and fibrosis. The expression pattern of inflammatory markers in tear fluids at baseline might serve as a prognostic factor for DAOSD.

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“…Conjunctival scar prevention or modification remains a therapeutic concern in ophthalmology. TGF-β, IL-6 [19] , MCP-1 [20] , VEGF [21] , connective tissue growth factor (CTGF) [22] , and the metalloproteinase family [23] are all implicated in the etiology of conjunctival scarring. The regulation of HTFs through growth factors [21][22] , inflammatory processes [24] , and/or fibroblast proliferation [2] is commonly used for the prevention of tissue fibrosis.…”

Section: Impairment Of Smads and Mapks Phosphorylationmentioning

confidence: 99%

“…Altogether, these results demonstrated that the inhibitory effects of 17β-estradiol on TGF-β-induced CGC might also be driven by comparable processes. IL-6 is a cytokine with pleiotropic effects that contributes to the control of lymphocyte activity and regulates the acutephase response [19] . Macrophages also play a crucial role in wound healing and scar formation [30] .…”

Section: Impairment Of Smads and Mapks Phosphorylationmentioning

confidence: 99%

17β-estradiol inhibits TGF-β-induced collagen gel contraction mediated by human Tenon fibroblasts via Smads and MAPK signaling pathways

Yang,

Li,

et al. 2023

Int J Ophthalmol

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AIM: To investigate the impact of 17β-estradiol on the collagen gels contraction (CGC) and inflammation induced by transforming growth factor (TGF)-β in human Tenon fibroblasts (HTFs). METHODS: HTFs were three-dimensionally cultivated in type I collagen-generated gels with or without TGF-β (5 ng/mL), 17β-estradiol (12.5 to 100 µmol/L), or progesterone (12.5 to 100 µmol/L). Then, the collagen gel diameter was determined to assess the contraction, and the development of stress fibers was analyzed using immunofluorescence staining. Immunoblot and gelatin zymography assays were used to analyze matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) being released into culture supernatants. Enzyme-linked immunosorbent assay (ELISA) and reverse transcription-quantitative polymerase chain reaction (RT-PCR) were used to detect interleukin (IL)-6, monocyte chemoattractant proteins (MCP)-1, and vascular endothelial growth factor (VEGF) in HTFs at the translational and transcriptional levels. The phosphorylation levels of Sma- and Mad-related proteins (Smads), mitogen-activated protein kinases (MAPKs), and protein kinase B (AKT) were measured by immunoblotting. Statistical analysis was performed using either the Tukey-Kramer test or Student's unpaired t-test to compare the various treatments. RESULTS: The CGC caused by TGF-β in HTFs was significantly inhibited by 17β-estradiol (25 to 100 µmol/L), and a statistically significant difference was observed when comparing the normal control group with 17β-estradiol concentrations exceeding 25 µmol/L (P<0.05). The suppressive impact of 17β-estradiol became evident 24h after administration and peaked at 72h (P<0.05), whereas progesterone had no impact. Moreover, 17β-estradiol attenuated the formation of stress fibers, and the production of MMP-3 and MMP-1 in HTFs stimulated by TGF-β. The expression of MCP-1, IL-6, and VEGF mRNA and protein in HTFs were suppressed by 100 µmol/L 17β-estradiol (P<0.01). Additionally, the phosphorylation of Smad2 Smad3, p38, and extracellular signal-regulated kinase (ERK) were downregulated (P <0.01). CONCLUSION: 17β-estradiol significantly inhibits the CGC and inflammation caused by TGF-β in HTFs. This inhibition is likely related to the suppression of stress fibers, inhibition of MMPs, and attenuation of Smads and MAPK (ERK and p38) signaling. 17β-estradiol may have potential clinical benefits in preventing scar development and inflammation in the conjunctiva.

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Potential roles of the IL-6 family in conjunctival fibrosis

Cited by 7 publications

References 28 publications

Mycobiome Dysbiosis in Women with Intrauterine Adhesions

Mycobiome Dysbiosis in Women with Intrauterine Adhesions

Dupilumab‐associated ocular surface disease is characterized by a shift from Th2/Th17 toward Th1/Th17 inflammation

17β-estradiol inhibits TGF-β-induced collagen gel contraction mediated by human Tenon fibroblasts via Smads and MAPK signaling pathways

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