Glycogen synthase kinase 3 in chronic rhinosinusitis: two faces of a single enzyme in one disease

Linke, Robert; Pries, Ralph; Könnecke, Michael; Bruchhage, Karl‐Ludwig; Böscke, Robert; Gebhard, Maximilian; Wollenberg, Barbara

doi:10.1016/j.anai.2012.11.016

Cited by 7 publications

(3 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, in monocytes, PI3K/Akt-dependent inhibition of GSK3b activity can regulate TLR-dependent activation (31). In this study, we identi- number of pathological conditions, including chronic inflammatory diseases (32). In fact, in vivo administration of LiCl 2 to mice ameliorated inflammation and decreased the synthesis of inflammatory molecules and the extent of tissue damage (33).…”

Section: Discussionmentioning

confidence: 88%

LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3β Signaling–Dependent Notch Pathway

Verma

Fazil

Ong

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

In this study, we report that the integrin LFA-1 cross-linking with its ligand ICAM-1 in human PBMCs or CD4+ T cells promotes Th1 polarization by upregulating IFN-γ secretion and T-bet expression. LFA-1 stimulation in PBMCs, CD4+ T cells, or the T cell line HuT78 activates the Notch pathway by nuclear translocation of cleaved Notch1 intracellular domain (NICD) and upregulation of target molecules Hey1 and Hes1. Blocking LFA-1 by a neutralizing Ab or specific inhibition of Notch1 by a γ-secretase inhibitor substantially inhibits LFA-1/ICAM-1–mediated activation of Notch signaling. We further demonstrate that the Notch pathway activation is dependent on LFA-1/ICAM-1–induced inactivation of glycogen synthase kinase 3β (GSK3β), which is mediated via Akt and ERK. Furthermore, in silico analysis in combination with coimmunoprecipitation assays show an interaction between NICD and GSK3β. Thus, there exists a molecular cross-talk between LFA-1 and Notch1 through the Akt/ERK–GSK3β signaling axis that ultimately enhances T cell differentiation toward Th1. Although clinical use of LFA-1 antagonists is limited by toxicity related to immunosuppression, these findings support the concept that Notch inhibitors could be attractive for prevention or treatment of Th1-related immunologic disorders and have implications at the level of local inflammatory responses.

show abstract

Section: Discussionmentioning

confidence: 88%

LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3β Signaling–Dependent Notch Pathway

Verma

Fazil

Ong

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Glycogen synthase kinase 3 is an important regulator of inflammatory processes involved in promoting the production of inflammatory cytokines (TNF, IL-1β, IL-6). A high expression of phosphorylated GSK-3 was detected in the nasal polyp tissue of patients with CRSwNP compared with healthy mucosa [ 47 ]. Recent studies have shown that the monoterpene oxide 1,8-cineol is able to negatively modulate the Wnt/β-catenin signaling pathway by GSK-3 dephosphorylation in nasal polyps of chronic rhinosinusitis patients [ 48 ].…”

Section: Intra-cellular Signaling Transduction Mechanisms Underlyimentioning

confidence: 99%

Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

Chiarella

Lombardo

Lobello

et al. 2020

IJMS

View full text Add to dashboard Cite

Chronic rhinosinusitis is a common inflammatory disease of paranasal sinuses, which causes rhinorrhea, nasal congestion, and hyposmia. The genetic predisposition or the exposure to irritants can sustain the inflammatory response and the development of nasal polyposis. Nasal polyps are benign and teardrop-shaped growths that project in the nasal cavities, and originate from the ethmoid sinuses. This inflammatory process is associated with high expression of IL-4, IL-5 and IL-13 and IgE. Antibodies targeting these cytokines or receptors represent a therapeutic strategy in the treatment of nasal polyposis in combination with corticosteroids. The molecular pathogenesis of nasal polyps in chronic rhinosinusitis (CRS) patients is associated with remodeling transition, a process in which epithelial cells lose their typical phenotype, acquiring a mesenchymal-like aspect. TGFβ/SMAD, ERK, and Wnt/β-catenin pathways are altered during the nasal tissue remodeling. miRNA and inhibitor molecules targeting these signaling pathways are able to interfere with the process; which could lead to alternative therapies. Nasal polyps are an alternative source of mesenchymal stem cells, which can be isolated from surgical biopsies. A molecular understanding of the biology of PO-MSCs will contribute to the delineating inflammatory process underlying the development of nasal polyps.

show abstract

“…GSK‐3 is a highly conserved serine/threonine protein kinase found in all eukaryotes, which exists in two isoforms, namely GSK‐3α and GSK‐3β . GSK‐3β is implicated in several diseases, such as neurodegenerative diseases, cancer, inflammation and cardiovascular disease . Recently, some reports found that GSK‐3β might be involved in the pathogenesis of CRSwNP, and the underlying mechanisms remain unknown .…”

Section: Introductionmentioning

confidence: 99%

GSK‐3β activation index is a potential indicator for recurrent inflammation of chronic rhinosinusitis without nasal polyps

Hong

Chen

Qiao

et al. 2017

J Cellular Molecular Medi

View full text Add to dashboard Cite

Chronic rhinosinusitis without nasal polyps (CRSsNP) is one of the most common otorhinolaryngologic diseases worldwide. However, the underlying mechanism remains unclear. In this study, the expression of glycogen synthase kinase 3 (GSK‐3) was quantitatively evaluated in patients with CRSsNP (n = 20) and healthy controls (n = 20). The mRNA levels of GSK‐3α and GSK‐3β were examined by qPCR, the immunoreactivities of GSK‐3β and nuclear factor‐κB (NF‐κB) were examined by immunohistochemistry (IHC) staining, and the protein levels of GSK‐3β, phospho‐GSK‐3β (p‐GSK‐3β, s9) and NF‐κB were examined using Western blot analysis. We found that GSK‐3 was highly expressed in both CRSsNP and control groups without significant difference in both GSK‐3β mRNA and protein levels. However, when compared with healthy control group, the GSK‐3β activation index, defined as the ratio of GSK‐3β over p‐GSK‐3β, was significantly decreased, whereas the NF‐κB protein abundance was significantly increased in CRSsNP group (P < 0.05). Strikingly, the GSK‐3β activation index, was highly correlated with NF‐κB protein level, as well as CT scores in CRSsNP group (P < 0.05). It was also highly correlated with the mRNA expressions of inflammation‐related genes, including T‐bet, IFN‐γ and IL‐4 in CRSsNP group (P < 0.05). Our findings suggest that GSK‐3β activation index, reflecting the inhibitory levels of GSK‐3β through phosphorylation, may be a potential indicator for recurrent inflammation of CRSsNP, and that the insufficient inhibitory phosphorylation of GSK‐3β may play a pivotal role in the pathogenesis of CRSsNP.

show abstract

Glycogen synthase kinase 3 in chronic rhinosinusitis: two faces of a single enzyme in one disease

Cited by 7 publications

References 25 publications

LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3β Signaling–Dependent Notch Pathway

LFA-1/ICAM-1 Ligation in Human T Cells Promotes Th1 Polarization through a GSK3β Signaling–Dependent Notch Pathway

Nasal Polyposis: Insights in Epithelial-Mesenchymal Transition and Differentiation of Polyp Mesenchymal Stem Cells

GSK‐3β activation index is a potential indicator for recurrent inflammation of chronic rhinosinusitis without nasal polyps

Contact Info

Product

Resources

About