WZ3146 inhibits mast cell Lyn and Fyn to reduce IgE-mediated allergic responses in vitro and in vivo

Park, Young Hwan; Kim, Do Kyun; Kim, Hyuk Soon; Lee, Dajeong; Lee, Min Bum; Min, Keun Young; Jo, Min Geun; Lee, Ji Eon; Kim, Young Mi; Choi, Wahn Soo

doi:10.1016/j.taap.2019.114763

Cited by 17 publications

(9 citation statements)

References 37 publications

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“…These responses are found to manage osteoclast differentiation, insulin signaling pathway, pulmonary barrier integrity, liver regeneration, and proliferation of malignant melanoma cells [ 75 , 76 ]. This enzyme is also known to participate in inducing various inflammatory and allergic diseases via direct or indirect activation of NF-κB [ 77 , 78 , 79 ]. Lyn phosphorylates various proteins including Syk tyrosine kinase (at 317 residue) [ 80 ], PI3K/AKT [ 81 ], and TRAF-6/TAK-1 protein complex [ 55 ].…”

Section: Discussionmentioning

confidence: 99%

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

Ahuja

Kim

Sung

et al. 2020

IJMS

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Toll-like receptor 4 (TLR4) signaling is an important therapeutic target to manage lipopolysaccharide (LPS)-induced inflammation. The transcription factor signal transducer and activator of transcription 3 (STAT3) has been identified as an important regulator of various immune-related diseases and has generated interest as a therapeutic target. Here, we investigated the time-dependent roles of STAT3 in LPS-stimulated RAW264.7 macrophages. STAT3 inhibition induced expression of the pro-inflammatory genes iNOS and COX-2 at early time points. STAT3 depletion resulted in regulation of nuclear translocation of nuclear factor (NF)-κB subunits p50 and p65 and IκBα/Akt/PI3K signaling. Moreover, we found that one Src family kinase, Lyn kinase, was phosphorylated in STAT3 knockout macrophages. In addition to using pharmacological inhibition of NF-κB, we found out that STAT3KO activation of NF-κB subunit p50 and p65 and expression of iNOS was significantly inhibited; furthermore, Akt tyrosine kinase inhibitors also inhibited iNOS and COX-2 gene expression during early time points of LPS stimulation, demonstrating an NF-κB- Akt-dependent mechanism. On the other hand, iNOS expression was downregulated after prolonged treatment with LPS. Activation of NF-κB signaling was also suppressed, and consequently, nitric oxide (NO) production and cell invasion were repressed. Overall, our data indicate that STAT3 differentially regulates early- and late-phase TLR4-mediated inflammatory responses.

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Section: Discussionmentioning

confidence: 99%

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

Ahuja

Kim

Sung

et al. 2020

IJMS

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“…Some findings have suggested that anaphylactic reaction can be reduced by inhibiting mast cell activation ( 37 ). Several approaches have been reported to stabilized mast cells by targeting KIT ( 38 ), Fyn and Lyn ( 39 ), reducing IgE ( 40 ), etc. This study showed that safranal stabilized mast cells by decreasing degranulation and production of inflammatory mediators IL-6, TNF-α, and LTC 4 .…”

Section: Discussionmentioning

confidence: 99%

Safranal Alleviated OVA-Induced Asthma Model and Inhibits Mast Cell Activation

Lertnimitphun

Zhang

et al. 2021

Front. Immunol.

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IntroductionAsthma is a chronic and recurring airway disease, which related to mast cell activation. Many compounds derived from Chinese herbal medicine has promising effects on stabilizing mast cells and decreasing inflammatory mediator production. Safranal, one of the active compounds from Crocus sativus, shows many anti-inflammatory properties. In this study, we evaluated the effect of safranal in ovalbumin (OVA)-induced asthma model. Furthermore, we investigate the effectiveness of safranal on stabilizing mast cell and inhibiting the production of inflammatory mediators in passive systemic anaphylaxis (PSA) model.MethodsOVA-induced asthma and PSA model were used to evaluate the effect of safranal in vivo. Lung tissues were collected for H&E, TB, IHC, and PAS staining. ELISA were used to determine level of IgE and chemokines (IL-4, IL-5, TNF-α, and IFN-γ). RNA sequencing was used to uncovers genes that safranal regulate. Bone marrow-derived mast cells (BMMCs) were used to investigate the inhibitory effect and mechanism of safranal. Cytokine production (IL-6, TNF-α, and LTC4) and NF-κB and MAPKs signaling pathway were assessed.ResultsSafranal reduced the level of serum IgE, the number of mast cells in lung tissue were decreased and Th1/Th2 cytokine levels were normalized in OVA-induced asthma model. Furthermore, safranal inhibited BMMCs degranulation and inhibited the production of LTC4, IL-6, and TNF-α. Safranal inhibits NF-κB and MAPKs pathway protein phosphorylation and decreases NF-κB p65, AP-1 nuclear translocation. In the PSA model, safranal reduced the levels of histamine and LTC4 in serum.ConclusionsSafranal alleviates OVA-induced asthma, inhibits mast cell activation and PSA reaction. The possible mechanism occurs through the inhibition of the MAPKs and NF-κB pathways.

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“…GSK2646264 is another Syk inhibitor, which effectively prevents MCs activation; however, at present, it has not entered clinical trials due to its potential toxicity [ 146 ]. EGFR inhibitors WZ3146 can inhibit the activation of MCs in vitro through non-targeted antagonism of Lyn and Fyn [ 147 ]. AZD7762 can also inhibit the activity of Lyn/Fyn, but it has been reported to have cardiotoxicity ( Table 1 ) [ 148 ].…”

Section: Future Prospects In the Manipulation Of The Mcs Functionsmentioning

confidence: 99%

Two Sides of the Coin: Mast Cells as a Key Regulator of Allergy and Acute/Chronic Inflammation

Zhang

Kurashima

2021

Cells

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It is well known that mast cells (MCs) initiate type I allergic reactions and inflammation in a quick response to the various stimulants, including—but not limited to—allergens, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). MCs highly express receptors of these ligands and proteases (e.g., tryptase, chymase) and cytokines (TNF), and other granular components (e.g., histamine and serotonin) and aggravate the allergic reaction and inflammation. On the other hand, accumulated evidence has revealed that MCs also possess immune-regulatory functions, suppressing chronic inflammation and allergic reactions on some occasions. IL-2 and IL-10 released from MCs inhibit excessive immune responses. Recently, it has been revealed that allergen immunotherapy modulates the function of MCs from their allergic function to their regulatory function to suppress allergic reactions. This evidence suggests the possibility that manipulation of MCs functions will result in a novel approach to the treatment of various MCs-mediated diseases.

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WZ3146 inhibits mast cell Lyn and Fyn to reduce IgE-mediated allergic responses in vitro and in vivo

Cited by 17 publications

References 37 publications

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

STAT3 Differentially Regulates TLR4-Mediated Inflammatory Responses in Early or Late Phases

Safranal Alleviated OVA-Induced Asthma Model and Inhibits Mast Cell Activation

Two Sides of the Coin: Mast Cells as a Key Regulator of Allergy and Acute/Chronic Inflammation

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