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A novel eremophilane lactone inhibits FcεRI-dependent release of pro-inflammatory mediators: structure-dependent bioactivity

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Abstract

Background

Allergic inflammation is primarily mediated by immune effector cells such as mast cells and basophils that release proinflammatory cytokines. Both mast cells and basophils are activated via their high affinity IgE receptor (FcεRI) which initiates the release of proinflammatory mediators such as histamine and tumor necrosis factor (TNF). Considerable effort has been focused on finding an effective basophil stabilizer that inhibits the activation of FcεRI-activated mediator release. Recently, eremophilane lactones, a novel family of sesquiterpene compound originally isolated from Petasites japonicas (Sieb. et Zucc.), have been described, and it has been postulated that they may have anti-inflammatory activity, particularly in allergic disease.

Objective

Our objective was to determine the effect of two eremophilane lactones derived from 6β-angeloyloxy-3β,8-dihydroxyeremophil-7(11)-en-12,8β-olide (F-1) on immunoglobulin E (IgE)-dependent release of pro-inflammatory mediators by a basophil cell line, RBL-2H3, a model system for FcεRI-mediated activation of pro-inflammatory mediator release.

Methods

The parent compound (F-1) was chemically modified to produce F-1a [6β-angeloyloxy-3β-benzoyloxy-8-hydroxyeremophil-7(11)-en-12,8β-olide] and F-1b [6β-angeloyloxy-3β,8-diacetoxyeremophil-7(11)-en-12,8β-olide]. RBL-2H3 cells were sensitized with DNP-specific IgE and then activated with DNP-BSA. The effect of these compounds on IgE-dependent basophil degranulation was assessed by measuring the release of β-hexosaminidase (b-hex). In addition, TNF release was measured via ELISA.

Results

The phenylacetyl reaction modified C-8 and produced F-1a whereas acetylation of F-1 produced F-1b. F-1a was not cytotoxic to RBL-2H3 cells even at 50 μM, but F-1b was slightly cytotoxic at 50 μM, reducing viability of the cells by approximately 15 %. Neither F-1a nor F-1b inhibited FcεRI-dependent activation of RBL-2H3 cells when the cells were pretreated for only 30 min with the compounds. However, 24 h pretreatment with F-1a inhibited antigen-dependent degranulation by as much as 60 % and TNF production by as much as 90 %. F-1b had no effect on RBL-2H3 activation via FcεRI.

Conclusions

These results indicate that F-1a inhibits degranulation of RBL-2H3 cells activated via the high affinity IgE receptor, FcεRI, and that this effect is dependent upon hydroxylation of the third carbon.

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Acknowledgments

We thank Priyanka Pundir and Clayton MacDonald for technical assistance and helpful discussions during the course of this project.

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Authors and Affiliations

  1. National Institute for Nanotechnology, 11421 Saskatchewan Dr., Edmonton, T6G 2M9, AB, Canada

    M. Kulka

  2. Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Fei Qian, Gujiang Guo & Yiming Li

Authors
  1. Fei Qian
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  2. Gujiang Guo
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  3. Yiming Li
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  4. M. Kulka
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Corresponding author

Correspondence to M. Kulka.

Additional information

Responsible Editor: John Di Battista.

This work was supported by Canadian Institutes of Health Research and National Natural Science Foundation of China.

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Qian, F., Guo, G., Li, Y. et al. A novel eremophilane lactone inhibits FcεRI-dependent release of pro-inflammatory mediators: structure-dependent bioactivity. Inflamm. Res. 65, 303–311 (2016). https://doi.org/10.1007/s00011-016-0917-2

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  • DOI: https://doi.org/10.1007/s00011-016-0917-2

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