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Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to synovial inflammation and bone destruction by producing a pleiotropic cytokine interleukin-6 (IL-6). However, the molecular mechanisms through which IL-6 propels RASFs to contribute to bone loss are not fully understood. In the present study, we investigated the effect of IL-6 and IL-6 receptor (IL-6/IL-6R)-induced trans-signaling in human RASFs. IL-6 trans-signaling caused a significant increase in tartrate-resistant acid phosphatase (TRAP)-positive staining in RASFs and enhanced pit formation by ~3-fold in the osteogenic surface . IL-6/IL-6R caused dose-dependent increase in expression and nuclear translocation of transcription factor Ets2, which correlated with the expression of osteoclast-specific signature proteins RANKL, cathepsin B (CTSB), and cathepsin K (CTSK) in RASFs. Chromatin immunoprecipitation (ChIP) analysis of and promoters showed direct Ets2 binding and transcriptional activation upon IL-6/IL-6R stimulation. Knockdown of Ets2 significantly inhibited IL-6/IL-6R-induced RANKL, CTSB, and CTSK expression and TRAP staining in RASFs and suppressed markers of RASF invasive phenotype such as Thy1 and podoplanin (PDPN). Mass spectrometry analysis of the secretome identified 113 proteins produced by RASFs uniquely in response to IL-6/IL-6R that bioinformatically predicted its impact on metabolic reprogramming towards an osteoclast-like phenotype. These findings identified the role of Ets2 in IL-6 trans-signaling induced molecular reprogramming of RASFs to osteoclast-like cells and may contribute to RASF heterogeneity.
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http://dx.doi.org/10.3389/fimmu.2021.746503 | DOI Listing |
Exp Eye Res
December 2024
Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
Intraocular pressure (IOP) is regulated through the balance of production and drainage of aqueous humor. The main route of aqueous-humor outflow comprises the trabecular meshwork (TM) and Schlemm's canal (SC). We reported that IL-6 trans-signaling can inhibit TGF-β signaling in TM cells and may affect regulation of IOP.
View Article and Find Full Text PDFInvest Ophthalmol Vis Sci
December 2024
Center for Biotechnology & Genomic Medicine, Augusta University, Augusta, Georgia, United States.
Purpose: Interleukin-6 (IL-6) is an inflammatory cytokine implicated in various retinal pathologies and functions primarily through two signaling pathways: cis-signaling via IL-6 binding to its membrane-bound receptor (IL-6Rα), and trans-signaling via IL-6 binding to soluble IL-6 receptor (sIL-6R). Because the differential effects of IL-6 signaling in retinal Müller glial cells (MGCs) remain unclear, we generated an MGC-specific Il6ra-/- knockout (KO) mouse to eliminate IL-6Rα and, consequently, IL-6 cis-signaling in MGCs. In this study, we examined the proteomic changes in MGCs isolated from KO mice lacking a functional IL-6Rα.
View Article and Find Full Text PDFCell Rep
November 2024
QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, QLD 4072, Australia; School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, QLD 4000, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, QLD 4072, Australia. Electronic address:
A poor maternal diet during pregnancy predisposes the infant to severe lower respiratory tract infections (sLRIs), which, in turn, increases childhood asthma risk; however, the underlying mechanisms remain poorly understood. Here, we show that the offspring of high-fat diet (HFD)-fed mothers (HFD-reared pups) developed an sLRI following pneumovirus inoculation in early life and subsequent asthma in later life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyperneutropoiesis in the liver and elevated inflammatory cytokine expression, most notably granulocyte-colony stimulating factor (G-CSF), interleukin-17A (IL-17A), IL-6 and soluble IL-6 receptor (sIL-6R) (indicative of IL-6 trans-signaling) in the circulation and multiple organs but most prominently the liver.
View Article and Find Full Text PDFInt J Mol Sci
October 2024
Department of Infectious Diseases (Internal Medicine II), Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania.
IL-6 remains a key molecule of the cytokine storms characterizing COVID-19, exerting both proinflammatory and anti-inflammatory effects. Emerging research underscores the significance of IL-6 trans-signaling over classical signaling pathways, which has shifted the focus of therapeutic strategies. Additionally, the synergistic action of TNF-α and IFN-γ has been found to induce inflammatory cell death through PANoptosis, further amplifying the severity of cytokine storms.
View Article and Find Full Text PDFContemp Oncol (Pozn)
August 2024
Institute of Clinical Biochemistry, Hannover Medical School (MHH), Hannover, Germany.
Introduction: The cytokine interleukin-11 (IL-11) binds on its target cells to a membrane-bound IL-11R, which results in homodimerization of the signal-transducing β-receptor gp130. Recent studies have uncovered a pro- inflammatory role in several diseases, including different tumor entities, and mouse models have revealed a crucial role of the IL-11/IL-11R axis in gastric cancer. However, studies regarding human gastric cancer are sparse, and whether the results obtained in mouse models also hold true in the human situation is little investigated.
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