Iκ-B Kinase-2 Inhibitor Blocks Inflammation in Human Airway Smooth Muscle and a Rat Model of Asthma

Birrell, Mark A.; Hardaker, Elizabeth; Wong, Sing‐Wai; McCluskie, Kerryn; Catley, Matthew C.; Alba, Jorge De; Newton, Robert; Haj‐Yahia, Saleem; Pun, K. Tao; Watts, Clarissa J.; Shaw, R. J.; Savage, Tony J.; Belvisi, Maria G.

doi:10.1164/rccm.200412-1647oc

Cited by 119 publications

(127 citation statements)

References 43 publications

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“…The data presented here indicate that IKK2 inhibitors exhibit only small effects on IFNdependent anti-HSV-1 activity, which is consistent with a previous observation that efficient replication of HSV-1 involves activation of the NF-κb pathway (35). Interestingly, the IKK2 inhibitor that was identified in our assay has been shown to block inflammation in human airway smooth muscle and in a rat model of asthma (36). Taken together, inhibitors of the NF-κb signaling pathway may present attractive approaches for the treatment of autoimmune disease.…”

Section: Discussionsupporting

confidence: 92%

Genomic-Based High Throughput Screening Identifies Small Molecules That Differentially Inhibit the Antiviral and Immunomodulatory Effects of IFN-α

Chen¹,

Zong

Cibotti³

et al. 2008

Mol Med

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Multiple lines of evidence suggest that inhibition of Type I Interferons, including IFN-α, may provide a therapeutic benefit for autoimmune diseases. Using a chemical genomics approach integrated with cellular and in vivo assays, we screened a small compound library to identify modulators of IFN-α biological effects. A genomic fingerprint was developed from both ex vivo patient genomic information and in vitro gene modulation from IFN-α cell-based stimulation. A high throughput genomic-based screen then was applied to prioritize 268 small molecule inhibitors targeting 41 different intracellular signaling pathways. Active compounds were profiled further for their ability to inhibit the activation and differentiation of human monocytes using disease-related stimuli. Inhibitors targeting NF-κB or Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling emerged as "dissociated inhibitors" because they did not modulate IFN-α anti-viral effects against HSV-1 but potently inhibited other immune-related functions. This work describes a novel strategy to identify small molecule inhibitors for the treatment of autoimmune disorders.

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Section: Discussionsupporting

confidence: 92%

Genomic-Based High Throughput Screening Identifies Small Molecules That Differentially Inhibit the Antiviral and Immunomodulatory Effects of IFN-α

Chen¹,

Zong

Cibotti³

et al. 2008

Mol Med

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“…Other data also contradict the idea that TZDs might act via the activation of GR. For example, DEX, even at very high concentrations, causes only a small inhibition of IL-1b stimulated the release of granulocytecolony stimulating factor from HASM cells, whereas the TZD, ciglitazone, virtually abolished it (20,54). Similarly, DEX exerts no effect on the IL-13-stimulated release of eotaxin (54), although TRO causes a marked inhibition of the IL-4-induced release of eotaxin (Figure 1).…”

Section: Discussionmentioning

confidence: 98%

“…Evidence also indicates that TZDs can modulate the activation of NF-kB under some circumstances (52,53), and the activation of NF-kB by TNF-a and IL-1b is known to play a role in the induction of inflammatory gene expression in HASM cells (54,55). To determine if the anti-inflammatory effects of TZDs in HASM cells are attributable to their effects on the activation of NF-kB, we assessed the impact of TZDs on the TNF-a-induced translocation of NF-kB p65.…”

Section: Role Of Erk and Nf-kbmentioning

confidence: 99%

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

Zhu¹,

Flynt

Ghosh

et al. 2011

Am J Respir Cell Mol Biol

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Airway smooth muscle (ASM) cells have been reported to contribute to the inflammation of asthma. Because the thiazolidinediones (TZDs) exert anti-inflammatory effects, we examined the effects of troglitazone and rosiglitazone on the release of inflammatory moieties from cultured human ASM cells. Troglitazone dosedependently reduced the IL-1b-induced release of IL-6 and vascular endothelial growth factor, the TNF-a-induced release of eotaxin and regulated on activation, normal T expressed and secreted (RANTES), and the IL-4-induced release of eotaxin. Rosiglitazone also inhibited the TNF-a-stimulated release of RANTES. Although TZDs are known to activate peroxisome proliferator-activated receptor-g (PPARg), these anti-inflammatory effects were not affected by a specific PPARg inhibitor (GW 9662) or by the knockdown of PPARg using short hairpin RNA. Troglitazone and rosiglitazone each caused the activation of adenosine monophosphate-activated protein kinase (AMPK), as detected by Western blotting using a phospho-AMPK antibody. The anti-inflammatory effects of TZDs were largely mimicked by the AMPK activators, 5-amino-4-imidazolecarboxamide ribose (AICAR) and metformin. However, the AMPK inhibitors, Ara A and Compound C, were not effective in preventing the antiinflammatory effects of troglitazone or rosiglitzone, suggesting that the effects of these TZDs are likely not mediated through the activation of AMPK. These data indicate that TZDs inhibit the release of a variety of inflammatory mediators from human ASM cells, suggesting that they may be useful in the treatment of asthma, and the data also indicate that the effects of TZDs are not mediated by PPARg or AMPK.

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“…Disruption of Nrf2 in mice was found to be more susceptible to allergen-mediated airway inflammation (5). Strategies targeting the NF-kB signaling pathway using NF-kBspecific decoy oligonucleotide, IKKb-selective small molecule inhibitor, and RIP-2 small interfering RNA have demonstrated beneficial effects in experimental asthma models (19,26). Compounds capable of promoting Nrf2 transcriptional activity have demonstrated protection against experimental asthma (5,17).…”

Section: Discussionmentioning

confidence: 99%

Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite–Induced Asthma

Peh

Chang

et al. 2015

The Journal of Immunology

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Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform γ-tocotrienol possesses both antioxidative and anti-inflammatory properties, we sought to determine protective effects of γ-tocotrienol in a house dust mite (HDM) experimental asthma model. BALB/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts, oxidative damage biomarkers, and cytokine levels. Lungs were examined for cell infiltration and mucus hypersecretion, as well as the expression of antioxidants and proinflammatory biomarkers. Sera were assayed for IgE and γ-tocotrienol levels. Airway hyperresponsiveness in response to methacholine was measured. γ-Tocotrienol displayed better free radical–neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil, and neutrophil counts in HDM mouse asthma in vivo, as compared with other vitamin E isoforms, including α-tocopherol. Besides, γ-tocotrienol abated HDM-induced elevation of BAL fluid cytokine and chemokine levels, total reactive oxygen species and oxidative damage biomarker levels, and of serum IgE levels, but it promoted lung-endogenous antioxidant activities. Mechanistically, γ-tocotrienol was found to block nuclear NF-κB level and enhance nuclear Nrf2 levels in lung lysates to greater extents than did α-tocopherol and prednisolone. More importantly, γ-tocotrienol markedly suppressed methacholine-induced airway hyperresponsiveness in experimental asthma. To our knowledge, we have shown for the first time the protective actions of vitamin E isoform γ-tocotrienol in allergic asthma.

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Iκ-B Kinase-2 Inhibitor Blocks Inflammation in Human Airway Smooth Muscle and a Rat Model of Asthma

Cited by 119 publications

References 43 publications

Genomic-Based High Throughput Screening Identifies Small Molecules That Differentially Inhibit the Antiviral and Immunomodulatory Effects of IFN-α

Genomic-Based High Throughput Screening Identifies Small Molecules That Differentially Inhibit the Antiviral and Immunomodulatory Effects of IFN-α

Anti-inflammatory Effects of Thiazolidinediones in Human Airway Smooth Muscle Cells

Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite–Induced Asthma

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