INTERNATIONAL IMMUNOPHARMACOLOGY
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2023
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IF 5.6
Shixin Duan,Jun Wang,Xinyi Lou,Dongxin Chen,Peiyunfeng Shi,Hongchao Jiang,Zhiming Wang,Wen Li,Feng Qian
As a crucial member of the Interleukin-1 (IL-1) family, IL-33 plays an indispensable role in modulating inflammatory responses. Here, we developed an effective anti-human IL-33 monoclonal antibody (mAb) named 5H8. Importantly, we have identified an epitope (FVLHN) of IL-33 protein as a recognition sequence for 5H8, which plays an important role in mediating the biological activity of IL-33. We observed that 5H8 significantly suppressed IL-33-induced IL-6 expression in bone marrow cells and mast cells in a dose-dependent manner in vitro. Furthermore, 5H8 effectively relieved HDM-induced asthma and PR8-induced acute lung injury in vivo. These findings indicate that targeting the FVLHN epitope is critical for inhibiting IL-33 function. In addition, we detected that the Tm value of 5H8 was 66.47℃ and the KD value was 173.0 pM, which reflected that 5H8 had good thermal stability and high affinity. Taken together, our data suggest that our newly developed 5H8 antibody has potential as a therapeutic antibody for treating inflammatory diseases.
研究领域:
免疫学
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药理学
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炎症
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PubMed
高影响因子
INFLAMMATION RESEARCH
·
2025
·Vol. 74
·期 1
·1-18
·
IF 5.4
Li Jue,Wu Zhijing,Li Nan,Wang Jianhong,Huang Meihua,Zhu Li,Wan Guiping,Zhang Zhenzhen
Endometriosis, a persistent inflammatory disease, is associated with pelvic or abdominal pain. The immune system and sensory nervous system show a synergistic effect on regulation of pain. In particular, Interleukin-33 (IL-33) is released as a danger signal and drives key hallmarks of severe endometriosis. To explore the mechanistic involvement of IL-33 in pain associated with endometriosis, both an in vivo murine endometriosis model and in vitro experiments with RAW 264.7 cells and dorsal root ganglion (DRG) neurons were utilized. In vivo, we demonstrated that IL-33 significantly exacerbated endometriosis and induced hyperalgesia in mice. By interacting with the ST2 receptor in macrophages, IL-33 enhanced the release of tumor necrosis factor α (TNF-α) and Interleukin 1β (IL-1β). This process set off an inflammatory cascade, which further facilitated macrophages recruitment and neurogenesis in ectopic lesions. As an ion channel expressed by nociceptors, transient receptor potential vanilloid 1 (TRPV1) expression was significantly increased in DRG in the presence of IL-33. In vitro, we confirmed that IL-33 elevated the release of TNF-α in macrophages. Ultimately, macrophage-derived TNF-α increased TRPV1 protein level in DRG neuronal cells through the TNFR1/p38 MAPK signaling pathway. Overall, these results revealed an inductive role of IL-33 in pain associated with endometriosis, and highlighted the interaction between macrophages and sensory neurons.
研究领域:
免疫学
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神经科学
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妇产科学
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PubMed
高影响因子
Open Life Sciences
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2024
·Vol. 19
·期 1
·
IF 1.7
Xiaokeya Yasen,Renaguli Aikebaier,Atiguli Maimaiti,Munire Mushajiang
Radiotherapy for treating breast cancer is associated with cardiac damage. This study aimed to investigate the role of the interleukin (IL)-33/soluble receptor ST2 (sST2) axis in radiation-induced cardiac injury. Expressions of IL-33 and sST2 were detected in breast cancer patients following radiotherapy, radiation-induced cardiac damaged mice model, and cardiomyocytes using quantitative real-time PCR (qRT-PCR) and immunohistochemical assay. Cardiac injury was evaluated through an ultrasound imaging system and hematoxylin & eosin staining. The transcriptional factor was assessed using dual-luciferase reporter assay and chromatin immunoprecipitation. The results indicated that IL-33 and sST2 were highly expressed in breast cancer patients, which further elevated post-6 months but reduced after 12 months of radiotherapy. Radiation induces cardiac dysfunction and elevated IL-33 and sST2 levels in a time-dependent manner. However, silencing of IL-33 decreased sST2 expression to alleviate radiation-induced cardiac dysfunction. The IL-33 could be transcriptional activated by TCF7L2 by binding to IL33 promoter sites, which mutation alleviated cardiomyocyte injury caused by radiation. Additionally, radiation treatment resulted in higher levels of TCF7L2, IL-33, and sST2 in cardiomyocytes, and TCF7L2 knockdown reduced IL-33 and sST2 expression. In conclusion, TCF7L2 transcriptional-activated IL-33 mediated sST2 to regulate radiation-induced cardiac damage, providing novel insights into radiotherapy-induced cardiac damage.
Graphical abstract
研究领域:
肿瘤学
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心脏病学
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分子生物学
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Anti-Cancer Agents in Medicinal Chemistry
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2024
·Vol. 24
·期 15
·1142-1150
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IF 2.6
Wang Mingdong,Yin Jizhong,Han Qianyu,Li Bing,Zhao Xue-Wei,Xue Lei
Background: Non-Small Cell Lung Cancer (NSCLC) ranks as a leading cause of cancer-related mortality, necessitating the urgent search for cost-effective and efficient anti-NSCLC drugs. Our preliminary research has demonstrated that arsenic trioxide (ATO) significantly inhibits NSCLC
angiogenesis, exerting anti-tumor effects. In conjunction with existing literature reports, the Nrf2-IL-33 pathway is emerging as a novel mechanism in NSCLC angiogenesis. Objective: This study aimed to elucidate whether ATO can inhibit NSCLC angiogenesis through the Nrf2-IL-33 pathway.
Methods: Immunohistochemistry was employed to assess the expression of Nrf2, IL-33, and CD31 in tumor tissues from patients with NSCLC. DETA-NONOate was used as a nitric oxide (NO) donor to mimic high levels of NO in the tumor microenvironment. Western blot, quantitative real-time PCR,
and enzyme-linked immunosorbent assay were utilized to evaluate the expression of Nrf2 and IL-33 in the NCI-H1299 cell line. Subcutaneous xenograft models were established in nude mice by implanting NCI-H1299 cells to assess the anti-tumor efficacy of ATO. Results: High expression levels
of Nrf2 and IL-33 were observed in tumor samples from patients with NSCLC, and Nrf2 expression positively correlated with microvascular density in NSCLC. In vitro, NO (released from 1mM DETA-NONOate) promoted activation of the Nrf2-IL-33 signaling pathway in NCI-H1299 cells, which was
reversed by ATO. Additionally, both Nrf2 deficiency and ATO treatment significantly attenuated NOinduced IL-33 expression. In vivo, both ATO and the Nrf2 inhibitor ML385 demonstrated significant inhibitory effects on angiogenesis tumor growth. Conclusion: Nrf2-IL-33 signaling is
usually activated in NSCLC and positively correlates with tumor angiogenesis. ATO effectively disrupts the activation of the Nrf2-IL-33 pathway in NSCLC and thus inhibits angiogenesis, suggesting its potential as an anti-angiogenic agent for use in the treatment of NSCLC.
研究领域:
肿瘤学
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药理学
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分子生物学
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细胞生物学
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高影响因子
JOURNAL OF MEDICAL VIROLOGY
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2025
·Vol. 97
·期 6
·e70432
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IF 4.6
Qing Miao,Rui Yu,Fanyu Shi,Kaixin Li,Xinqian Du,Yinuo Gao,Yan Li,Ye Cui,Yan Chen,Jie Liu,Zhe Lv,Jing Yuan,Chris J. Corrigan,Sun Ying,Wei Wang
Respiratory syncytial virus (RSV) infection has been associated with disruption of the airway epithelial barrier, potentially increasing the risk of asthma development. However, whether and how RSV and RSV-induced IL-33 contribute to this process are still unclear. In vivo, 7-day-old C57BL/6 mice were infected perinasally with RSV, then viral replication, lung inflammation and barrier integrity were evaluated at various time points postinfection. In vitro, human epithelial cells were infected with RSV in the presence or absence of IL-33, and the expression and localization of apical junction complex proteins (AJC) were assessed by western blot analysis and immunofluorescence staining. The involvement of components of the IL-33/ST2/MyD88 axis was further verified through blockade of endogenous IL-33 signaling and pharmacological inhibition of MyD88. Exposure to RSV infection resulted in impairment of the airway epithelial barrier, as indicated by reduced expression of tight junction proteins (ZO-1, Occludin) and adherents junction protein (E-cadherin) in the lung tissues. These effects on epithelial barrier disruption were significantly attenuated in St2 -/- mice compared with wild-type controls. In vitro, the RSV-induced epithelial barrier disruption was exacerbated by topical application of exogenous IL-33, partially through activation of MyD88-mediated NF-κB signaling. Notably, knockdown of St2 by siRNA transfection or pharmacological inhibition of MyD88 partially restored the expression of E-cadherin, ZO-1 and Occludin in RSV-infected epithelial cells. RSV infection triggers robust IL-33 release from airway epithelial cells, leading to disrupted expression of AJC protein via activation of the MyD88-dependent NF-κB signaling pathway. These findings highlight the IL-33/ST2/MyD88 axis as a critical mediator of epithelial barrier dysfunction, which may represent a potential target for therapeutic intervention in RSV-mediated lung diseases.
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Cell Reports
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2026
·Vol. 45
·期 6
·
IF 7.7
Yifang Chen,Qian Zhang,Na Li,Zhaoqi Zhang,Tong Lei,Han Guo,Hezhe Lu,Yong Zhao
Dendritic cells (DCs) are professional antigen-presenting cells that exhibit significant heterogeneity in development and function. This study found that among 17 cytokines screened, only IL-33 could induce DCs to display a Th9-type cytokine profile, including IL-9, IL-4, and IL-13, in vitro . The response of DCs to IL-33 was synergistically enhanced by TGF-β and IL-4, defining a distinct subset termed DC9. Transcriptomic analysis revealed that DC9 possesses a unique gene expression signature, particularly in cytokine/chemokine clusters, compared to conventional DCs. Mechanistically, DC9 polarization depends on the JAK-STAT6-IRF4 signaling pathway. Functionally, DC9 preferentially drives naive CD4 + T cell differentiation toward Th9 cells in vitro . In an ovalbumin-induced allergic airway inflammatory mouse model, DC9 cells were detectable in lungs and adoptive transfer of DC9 exacerbated disease severity, and increased pulmonary Th9 cells. Collectively, we identify DC9 as a novel DC subset induced by IL-33/TGF-β/IL-4 through the JAK-STAT6-IRF4 axis, which promotes Th9 differentiation and aggravates allergic airway inflammation.
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Yixuan Li,Junyu Meng,Xi Wang,Rongtao Zhang,Xiaoying Wang,Yan Zhu,Jian Yang
Ethnopharmacological relevance Chronic Obstructive Pulmonary Disease (COPD) is a progressive respiratory disorder with complex pathogenesis and multiple contributing factors. Modified Fangji Huangqi decoction (MFJHQ), a traditional Chinese medicine formula, has demonstrated clinical efficacy in COPD treatment. However, the pharmacological roles and underlying mechanisms of MFJHQ in treating COPD remain unclear. Aim of study To investigate the therapeutic effects and molecular mechanisms of MFJHQ in the treatment of COPD. Methods COPD models were established in vitro using alveolar organoid (AOs) and 16 Human Bronchial Epithelial (16HBE) cells separately, induced by porcine pancreatic elastase (PPE) and in vivo in PPE-induced COPD mice. MFJHQ was administered via gavage for three weeks. RNA-sequencing and network pharmacology were employed to elucidate potential mechanisms of action. Results In vitro , MFJHQ enhanced epithelial barrier integrity by reducing permeability and upregulating zonula occludens-1 (ZO-1) expression. In vivo, MFJHQ effectively improved pulmonary function, alleviated emphysema and airway obstruction, and protected lung tissue structure from damage. Mechanistically, RNA-sequencing and network pharmacology predicted, and subsequent experiments confirmed, that MFJHQ inhibited PPE-induced IL-33 and its downstream NF-κB signaling and CXCL5 expression thereby reducing neutrophil recruitment in lung tissues. Conclusion MFJHQ ameliorates COPD progression by inhibiting neutrophil infiltration through suppression of IL-33 and CXCL5 providing a new multi-targeted therapeutic strategy for COPD.
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BMC Pharmacology & Toxicology
·
2024
·Vol. 25
·期 1
·1-12
·
IF 2.8
Tian Chunyan,Liu Qi,Zhang Xiaoyu,Li Zhuying
Background Calycosin, a flavonoid compound extracted from Astragalus membranaceus , has shown anti-asthma benefits in house dust mite-induced asthma. Recent studies have suggested that innate-type cells, including group 2 innate lymphoid cells (ILC2s) and macrophages, serve as incentives for type 2 immunity and targets for drug development in asthma. This work focuses on the effects of calycosin on the dysregulated ILC2s and macrophages in allergic asthma. Methods In vivo, the asthmatic mouse model was established with ovalbumin (OVA) sensitization and challenge, and calycosin was intraperitoneally administered at doses of 20 and 40 mg/kg. In vivo, mouse primary ILC2s were stimulated with interleukin (IL)-33 and mouse RAW264.7 macrophages were stimulated with IL-4 and IL-13 to establish the cell models. Cells were treated with calycosin at doses of 5 and 10 µM. Results In vivo, we observed significantly reduced numbers of eosinophils, neutrophils, monocyte macrophages and lymphocytes in the bronchoalveolar lavage fluid (BALF) of OVA-exposed mice with 40 mg/kg calycosin. Histopathological assessment showed that calycosin inhibited the airway inflammation and remodeling caused by OVA. Calycosin markedly decreased the up-regulated IL-4, IL-5, IL-13, IL-33, and suppression tumorigenicity 2 (ST2) induced by OVA in BALF and/or lung tissues of asthmatic mice. Calycosin repressed the augment of arginase 1 (ARG1), IL-10, chitinase-like 3 (YM1) and mannose receptor C-type 1 (MRC1) levels in the lung tissues of asthmatic mice. In vivo, calycosin inhibited the IL-33-induced activation as well as the increase of IL-4, IL-5, IL-13 and ST2 in ILC2s. Calycosin also repressed the increase of ARG1, IL-10, YM1 and MRC1 induced by IL-4 and IL-13 in RAW264.7 macrophages. In addition, we found that these changes were more significant in 40 mg/kg calycosin treatment than 20 mg/kg calycosin. Conclusions Collectively, this study showed that calycosin might attenuate OVA-induced airway inflammation and remodeling in asthmatic mice via preventing ILC2 activation and macrophage M2 polarization. Our study might contribute to further study of asthmatic therapy.
研究领域:
免疫学
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药理学
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呼吸病学
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高影响因子
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