Antiallergic and Anti-Inflammatory Effects of a Novel IκB Kinase β Inhibitor, IMD-0354, in a Mouse Model of Allergic Inflammation

Sugita, Akemi; Ogawa, Hirohisa; Azuma, Masahiko; Muto, Shoshi; Honjo, Akifumi; Yanagawa, Hiroaki; Nishioka, Yasuhiko; Tani, Kenji; Itai, Akiko; Sone, Saburo

doi:10.1159/000161579

Cited by 60 publications

(68 citation statements)

References 50 publications

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“…The production of eotaxin has also been reported to be mediated through NF-kB activation in a mouse model of allergic inflammation [28] and thus, in our study the blockade of the EGFR pathway could potentially have resulted from suppression of NF-kB activation followed by the reductions of IL-6, CINC-1 and eotaxin in BAL. Poynter et al reported that NF-kB repression selectively in airway epithelium significantly reduced the lymphocytes and eosinophils as well as eotaxin and IL-5 in BAL but did not alter AHR in a mouse model of asthma [29].…”

Section: Discussionmentioning

confidence: 65%

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

Tsuchiya

Takeda

et al. 2010

Eur J Immunol

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EGF receptor (EGFR) is involved in cell differentiation and proliferation in airways and may trigger cytokine production by T cells. We hypothesized that EGFR inhibition at the time of allergic sensitization may affect subsequent immune reactions. Brown Norway rats were sensitized with OVA, received the EGFR tyrosine kinase inhibitor, AG1478 from days 0 to 7 and OVA challenge on day 14. OVA-specific IgE in serum and cytokines and chemokines in BAL were measured 24 h after challenge. To evaluate effects on airway hyperresponsiveness (AHR), rats were sensitized, treated with AG1478, intranasally challenged, and then AHR was assessed. Furthermore chemotactic activity of BALF for CD4 1 T cells was examined. The eosinophils, neutrophils and lymphocytes in BAL were increased by OVA and only the lymphocytes were reduced by AG1478. OVA significantly enhanced IL-6 concentration in BAL, which was inhibited by AG1478. However AHR, OVA-specific IgE and IL-4 mRNA expression in CD4 1 T cells were not affected by AG1478. BALF from OVAsensitized/challenged rats induced CD4 1 T-cell migration, which was inhibited by both AG1478 treatment in vivo and neutralization of IL-6 in vitro. EGFR activation during sensitization may affect the subsequent influx of CD4 1 T cells to airways, mainly mediated through IL-6.Key words: Asthma . CD4 1 T cells . EGF receptors . IL-6Supporting Information available online IntroductionThe EGF receptor (EGFR) is involved in the regulation of cell differentiation and proliferation and in the pathogenesis of various diseases including epithelial tumors [1,2]. The importance of the EGFR axis in cancer has best been studied in breast malignancies. However, the EGFR signaling pathway is implicated in airway biology and EGFR is expressed by many cell types in the lung, including smooth muscle cells, endothelium, fibroblasts and epithelium [3,4]. Human asthmatic airways show increased EGFR immunoreactivity in airway epithelium, glands, and smooth muscle [5] and EGFR activation has been reported to promote epithelial repair and to induce mucin production and remodeling of airway tissues [6,7]. We previously reported that multiple OVA challenges increased protein expression of the EGFR ligand, heparin-binding EGF-like 1590growth factor (HB-EGF) in airway epithelium in Brown Norway (BN) rats [4]. The inhibition of the tyrosine kinase signaling cascade might have therapeutic effects in asthma [8].Ligands for the EGFR found in the lung include EGF, TGF-a, amphiregulin, epiregulin and HB-EGF, all of which are synthesized as transmembrane precursors and are proteolytically cleaved by metalloproteases such as ADAM 10 and ADAM 17 [3]. Binding of these ligands to the receptor causes activation of the tyrosine kinase and receptor autophosphorylation. AG1478, a selective inhibitor of the EGFR tyrosine kinase (EGFR-TK), prevents ligand-induced EGFR phosphorylation and has antitumor activity [9]. AG1478 inhibits the proliferation of lung fibroblasts in vitro and has protective effects against bleomycin and vanadium pento...

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Section: Discussionmentioning

confidence: 65%

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

Tsuchiya

Takeda

et al. 2010

Eur J Immunol

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“…However, there remains a concern that proteasome inhibition may affect other signaling pathways. IMD-0354 is a synthesized low molecular weight compound that specifically inhibits IKKb, inducing the inhibition of NF-kB activation only in inflammatory conditions, and it was proven that this drug does not inhibit other kinases, proteases, or proteasome-related immune responses (34). No IKKb inhibitor is known to be in the process of clinical application at present, except for IMD-1041, a prodrug of IMD-0354; a phase I study with the IMD-0354 capsule confirmed sufficient safety (20).…”

Section: Discussionmentioning

confidence: 99%

IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Antiangiogenic Treatment

Kinose

Sawada

Makino

et al. 2015

Molecular Cancer Therapeutics

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The prolongation of progression-free survival (PFS) in patients with advanced ovarian cancer by antiangiogenic therapy has been shown in several clinical trials. However, although an anti-VEGF antibody (bevacizumab) is the only option currently available, its efficacy is limited and it is not cost effective for use in all patients. Therefore, the development of a novel antiangiogenic drug, especially composed of smallmolecule compounds, could be a powerful armament for ovarian cancer treatment. As NF-kB signaling has the potential to regulate VEGF expression, we determined to identify whether VEGF expression is associated with NF-kB activation and to investigate the possibility of a novel IKKb inhibitor, IMD-0354 (IMMD Inc.), as an antiangiogenic drug. Tissue microarrays from 94 ovarian cancer tissues were constructed and immunohistochemical analyses performed. We revealed that IKK phosphorylation is an independent prognostic factor (PFS: 26

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“…9,21,22) This study revealed IMD-0354 dose-dependently attenuated neointimal formation after wire-mediated arterial injury in mice. Thus, IMD-0354 has the potential to prevent restenosis in humans with fewer adverse effects compared to conservative therapies.…”

Section: Discussionmentioning

confidence: 56%

“…The concentrations of the drug were determined according to previous reports. 9,11) Quantitative assessment of arterial neointima: Tissue sections were stained with hematoxylin and eosin (HE) and Elastica van Gieson (EvG). Light microscopic morphometric computer analysis was carried out.…”

Section: Methodsmentioning

confidence: 99%

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A Novel IKK Inhibitor Prevents Progression of Restenosis After Arterial Injury in Mice

et al. 2012

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SummaryRestenosis after percutaneous coronary intervention (PCI) is still a clinically serious problem. We examined the treatment efficacy of IMD-0354, a novel IKK inhibitor, on arteriopathy. Using C57BL/6J mice, a wire-injury model was prepared and the mice were intraperitoneally injected with IMD-0354 or vehicle twice a day. The vehicle-treated injured arteries showed significantly thickened intima (3.77 ± 0.59, n = 8), however, IMD-0354 suppressed its progression (1.62 ± 0.22, n = 10, P < 0.05) on day 28. While enhanced expression of PCNA and NF-κB was observed in the untreated injured arteries, IMD-0354 significantly suppressed their expressions. Quantitative RT-PCR revealed that the expression of several inflammatory factors was reduced in the arteries from mice which received IMD-0354 treatment compared with the control animals. Thus, this drug may effectively prevent restenosis after coronary intervention and other cardiovascular diseases. (Int Heart J 2012; 53: 133-138) Key words: IKK inhibitor, Chemical compound, Arterial remodeling, Inflammation, Smooth muscle R estenosis, which consists of neointimal formation after percutaneous coronary intervention (PCI), is a clinically serious problem. 1-3) Because inflammation is an essential pathological feature of neointimal formation, nuclear factor-kappa B (NF-κB) plays an important role in this process. 4) In humans, activated NF-κB is detected in restenotic lesions.5) Thus, NF-κB regulation has the potential to suppress its progression.Activation of NF-κB induces gene expression that leads to transactivation of adhesion molecules, cytokines and chemokines, promoting the inflammatory status involved in arterial injury. NF-κB is a dimer of the Rel family members and the most common active form is composed of p50 or p52 and p65. In resting cells, NF-κB is inactive and segregated in the cytoplasm, and bound to an inhibitory protein known as the inhibitor of NF-κB (IκB). NF-κB activation requires phosphorylation of IκB by IκB kinase (IKK) complex. The phosphorylated IκB is then ubiquitinated and degraded by proteasomes. Subsequently, the unbound NF-κB is translocated to the nucleus and binds to the promoter or enhancer of specific genes, including those involved in inflammatory reactions. 6)Recently, the first clinical use of an NF-κB decoy oligonucleotide at the site of coronary stenting for the prevention of restenosis was reported. 7,8) However, the indispensable role played by NF-κB in many biological processes has raised the concern that a complete shutdown of this pathway would have significant detrimental effects on normal cellular function. Instead, drugs that selectively target only inflammation-induced NF-κB activity would be of greater therapeutic value. IMD-0354, a novel NF-κB inhibitor, is a drug that specifically suppresses IKK-β activity.9) In this study, we investigated the effects of IMD-0354 on neointimal formation in vivo and VSMC proliferation in vitro. MethodsArterial injury models in mice: Male mice (C57BL/6, age 6-8 weeks, 20-25 g; Japa...

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Antiallergic and Anti-Inflammatory Effects of a Novel IκB Kinase β Inhibitor, IMD-0354, in a Mouse Model of Allergic Inflammation

Cited by 60 publications

References 50 publications

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

EGF receptor activation during allergic sensitization affects IL‐6‐induced T‐cell influx to airways in a rat model of asthma

IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Antiangiogenic Treatment

A Novel IKK Inhibitor Prevents Progression of Restenosis After Arterial Injury in Mice

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