Regulation and Possible Function of β-Catenin in Human Monocytes

Thiele, Andrea; Wasner, Mark; Müller, Claudia; Engeland, Kurt; Hauschildt, Sunna

doi:10.4049/jimmunol.167.12.6786

Cited by 35 publications

(34 citation statements)

References 61 publications

(66 reference statements)

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“…Indeed, the current authors observed that KGF prevents the OVA-induced decreased expression of both ZO-1 and b-catenin, two adaptors playing a key role in the formation of tight and adherens junctions, respectively. Their expressions were also identified in cell infiltrate within the bronchial mucosa; this might be due to their transient expressions by some inflammatory cells as previously reported [32,33]. One other function has been assigned to b-catenin, i.e.…”

Section: Discussionmentioning

confidence: 61%

Keratinocyte growth factor improves alterations of lung permeability and bronchial epithelium in allergic rats

Tillie‐Leblond¹,

Gosset²,

Berre³

et al. 2007

Eur Respir J

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Chronic allergic asthma is associated with marked inflammatory reaction, microvascular leakage and epithelium injury. As previously shown in a rat model of chronic asthma, these alterations increase lung permeability and distal airway fluid clearance. Keratinocyte growth factor (KGF) has been shown to induce epithelial cell proliferation and to protect from acute lung injuries. Therefore, the current authors evaluated the potential role of KGF treatment on lung permeability and airway inflammation in rats with chronic asthma.KGF (1 mg?kg -1 ) was administered intravenously before the last ovalbumin (OVA) challenge in sensitised rats. Permeability was assessed by the leak of radiolabelled albumin from the alveolar and systemic compartments. Histopathological analysis was also performed. Treatment with KGF decreased the leak of both markers and decreased the level of extravascular lung water in sensitised rats challenged with OVA. KGF treatment also reduced the inflammatory cell number in bronchoalveolar lavage fluid but not in bronchial mucosa. KGF markedly limited the allergen-induced alterations in epithelium integrity and the expression of the intercellular junction proteins b-catenin and zonula occludens protein-1.In conclusion, keratinocyte growth factor administration markedly limits lung permeability and airway inflammation, an effect associated with a decrease in epithelium alterations during chronic allergic asthma. These data open new prospects in the therapeutic strategy of asthma.

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Section: Discussionmentioning

confidence: 61%

Keratinocyte growth factor improves alterations of lung permeability and bronchial epithelium in allergic rats

Tillie‐Leblond¹,

Gosset²,

Berre³

et al. 2007

Eur Respir J

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“…by the adhesion process (35), although later, presumably as a response to DC differentiation signals, the levels of b-catenin decrease. In fact, GSK3 activity is crucial for the differentiation of monocytes into DCs and prevents their deviation to macrophage lineage (25) (results reported in this article), and the GM-CSF/IL-4 cytokine mixture should induce its activation.…”

Section: Discussionmentioning

confidence: 99%

Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features

Valencia

Hernández-López

Martínez

et al. 2011

The Journal of Immunology

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Dendritic cells (DCs) are critical regulators of immune responses that integrate signals from the innate and adaptive immune system and orchestrate T cell responses toward either immunity or tolerance. Growing evidence points to the Wnt signaling pathway as a pivotal piece in the immune balance and focuses on DCs as a direct target for their immunoregulatory role. Our results show that the increase in Wnt5a signaling during the differentiation of human DCs from monocytes alters their phenotype and compromises their subsequent capacity to mature in response to TLR-dependent stimuli. These Wnt5a-DCs produce scant amounts of IL-12p70 and TNF-α but increased levels of IL-10. Consequently, these Wnt5a-DCs have a reduced capacity to induce Th1 responses that promote IL-10 secretion by CD4 T cells. Changes in the transcriptional profile of Wnt5a-DCs correlate with their unconventional phenotype caused presumably by increased IL-6/IL-10 signaling during the process of DC differentiation. The effect of Wnt5a is not a consequence of β-catenin accumulation but is dependent on noncanonical Ca2+/calmodulin-dependent protein kinase II/NF-κB signaling. Our results therefore suggest that under high levels of Wnt5a, typical of the inflammatory state and sepsis, monocytes could differentiate into unconventional DCs with tolerogenic features.

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“…Other roles, however, have been described. For example, studies in human monocytes and THP-1 monocyte cells show that Wnt3a activation of the canonical Wnt signaling pathway did not result in TCF-promoter activity or the expression of classical Wnt target genes (23,24). Yet, induction of cytoplasmic ␤-cat upon exposure of human monocytes to Wnt3a resulted in a decrease in direct monocyte adherence to endothelial cells and subsequent transendothelial migration (24).…”

Section: Discussionmentioning

confidence: 99%

Canonical Wnt signaling negatively regulates platelet function

Steele

Harper

Macaulay

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Wnts regulate important intracellular signaling events, and dysregulation of the Wnt pathway has been linked to human disease. Here, we uncover numerous Wnt canonical effectors in human platelets where Wnts, their receptors, and downstream signaling components have not been previously described. We demonstrate that the Wnt3a ligand inhibits platelet adhesion, activation, dense granule secretion, and aggregation. Wnt3a also altered platelet shape change and inhibited the activation of the small GTPase RhoA. In addition, we found the Wnt-␤-catenin signaling pathway to be functional in platelets. Finally, disruption of the Wnt Frizzled 6 receptor in the mouse resulted in a hyperactivatory platelet phenotype and a reduced sensitivity to Wnt3a. Taken together our studies reveal a novel functional role for Wnt signaling in regulating anucleate platelet function and may provide a tractable target for future antiplatelet therapy.Wnt-␤-catenin pathway ͉ integrin ␣IIb␤3 ͉ frizzled 6 knockout mice A nucleate platelets are the principle effectors of haemostasis and are found circulating in a nonadhesive, quiescent state. At sites of vascular damage, platelets adhere to various exposed subendothelial matrix proteins and are activated, converting from a resting, discoid shape into larger, flattened structures with extended pseudopodia (1). Such activated platelets secrete and synthesize further agonists, inflammatory mediators, and vasoactive substances and through conformational changes in their major integrin receptor, ␣IIb␤3, aggregate to other platelets via fibrinogen (Fb) to form a haemostatic plug (2). Aberrant platelet activation can cause pathological thrombus formation, leading to thrombosis and ultimately vessel occlusion and tissue ischemia, the processes underlying myocardial infarction and stroke. Understanding the regulation of platelet activity is thus fundamental to comprehending thrombotic disorders and developing therapeutic strategies.The mammalian Wnt gene family is comprised of 19 secreted Wnt glycoproteins, which play essential roles in cell proliferation, cell-fate determination, and cell-fate differentiation during embryonic development and adult homeostasis (3, 4). These Wnt ligands activate a number of different signaling pathways via distinct receptors and downstream effectors to mediate effects on gene transcription and cell adhesion/migration (5, 6). For the Wnt-␤-catenin (␤-cat) signaling pathway (Fig. 1A), traditionally referred to as the ''canonical'' pathway, Wnts bind to a surface receptor complex comprised of a Frizzled (Fzd) receptor and the Lipoprotein Receptor-related Protein 5/6 (LRP5/6) coreceptor (5, 7). The signal is then transduced to the cytoplasmic protein Dishevelled (Dvl) where downstream pathways regulate the stability of ␤-cat (5, 7). In the absence of Wnt, ␤-cat is phosphorylated by a destruction complex containing Casein Kinase 1 (CK1), Glycogen Synthase Kinase 3␤ (GSK3␤), Axin-1, FRAT-1, and Adenomatous Polyposis Coli (APC), which targets ␤-cat for degradation via ubiquitina...

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Regulation and Possible Function of β-Catenin in Human Monocytes

Cited by 35 publications

References 61 publications

Keratinocyte growth factor improves alterations of lung permeability and bronchial epithelium in allergic rats

Keratinocyte growth factor improves alterations of lung permeability and bronchial epithelium in allergic rats

Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features

Canonical Wnt signaling negatively regulates platelet function

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