Pimecrolimus reduces eosinophil activation associated with calcium mobilization

Douglas A. Plager, Susan A. Henke, Yoshinori Matsuwaki, Arvind Madaan, Diane L. Squillace, Ross A. Dierkhising, Hirohito Kita

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Pimecrolimus is a calcineurin inhibitor that inhibits T cell and mast cell activation and effectively treats atopic dermatitis. However, its effects on eosinophils, a cell type implicated in allergic disease pathology, are unknown. Therefore, we examined the effects of pimecrolimus on eosinophil superoxide anion production, degranulation and survival. Methods: Purified eosinophils from normal or atopic donors were incubated with serial dilutions of pimecrolimus (μM to nM) and then stimulated with platelet activating factor (PAF), interleukin 5 (IL5), secretory immunoglobulin A (sIgA) or Alternaria alternata (Alt) fungus extract. Eosinophil activation was monitored by cytochrome c reduction resulting from superoxide anion production and by a 2-site immunoassay for eosinophil-derived neurotoxin (EDN) in cellular supernatants, as a marker of degranulation. Eosinophil survival was measured by propidium iodide exclusion using flow cytometry after 4 days in culture. Results: Normal and atopic eosinophil superoxide anion production induced by PAF, and associated with increased intracellular calcium, was inhibited up to 37% with 1 μM pimecrolimus. However, superoxide anion production induced by IL5 and sIgA was not consistently inhibited. EDN release, which ultimately depends on calcium, was inhibited about 30% with PAF, IL5 and sIgA stimulation for normal and atopic donor eosinophils. Furthermore, calcium-dependent Alt-induced EDN release was inhibited up to 49% with nanomolar pimecrolimus. Finally, increased eosinophil survival promoted by IL5 and sIgA was not influenced by pimecrolimus. Conclusion: Pimecrolimus moderately inhibits eosinophil superoxide anion production and EDN release associated with calcium mobilization, which may contribute to its efficacy in treating atopic dermatitis.

Original languageEnglish (US)
Pages (from-to)119-126
Number of pages8
JournalInternational Archives of Allergy and Immunology
Volume149
Issue number2
DOIs
StatePublished - May 2009

Fingerprint

Eosinophils
Eosinophil-Derived Neurotoxin
Calcium
Secretory Immunoglobulin A
Superoxides
Interleukin-5
Platelet Activating Factor
Atopic Dermatitis
pimecrolimus
Alternaria
Propidium
Cytochromes c
Immunoassay
Mast Cells
Flow Cytometry
Fungi
Pathology
T-Lymphocytes

Keywords

  • Alternaria alternate
  • Atopic dermatitis
  • Calcineurin inhibitor
  • Eosinophil
  • Fungus
  • Pimecrolimus

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Plager, D. A., Henke, S. A., Matsuwaki, Y., Madaan, A., Squillace, D. L., Dierkhising, R. A., & Kita, H. (2009). Pimecrolimus reduces eosinophil activation associated with calcium mobilization. International Archives of Allergy and Immunology, 149(2), 119-126. https://doi.org/10.1159/000189194

Pimecrolimus reduces eosinophil activation associated with calcium mobilization. / Plager, Douglas A.; Henke, Susan A.; Matsuwaki, Yoshinori; Madaan, Arvind; Squillace, Diane L.; Dierkhising, Ross A.; Kita, Hirohito.

In: International Archives of Allergy and Immunology, Vol. 149, No. 2, 05.2009, p. 119-126.

Research output: Contribution to journalArticle

Plager, DA, Henke, SA, Matsuwaki, Y, Madaan, A, Squillace, DL, Dierkhising, RA & Kita, H 2009, 'Pimecrolimus reduces eosinophil activation associated with calcium mobilization', International Archives of Allergy and Immunology, vol. 149, no. 2, pp. 119-126. https://doi.org/10.1159/000189194
Plager DA, Henke SA, Matsuwaki Y, Madaan A, Squillace DL, Dierkhising RA et al. Pimecrolimus reduces eosinophil activation associated with calcium mobilization. International Archives of Allergy and Immunology. 2009 May;149(2):119-126. https://doi.org/10.1159/000189194
Plager, Douglas A. ; Henke, Susan A. ; Matsuwaki, Yoshinori ; Madaan, Arvind ; Squillace, Diane L. ; Dierkhising, Ross A. ; Kita, Hirohito. / Pimecrolimus reduces eosinophil activation associated with calcium mobilization. In: International Archives of Allergy and Immunology. 2009 ; Vol. 149, No. 2. pp. 119-126.
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abstract = "Background: Pimecrolimus is a calcineurin inhibitor that inhibits T cell and mast cell activation and effectively treats atopic dermatitis. However, its effects on eosinophils, a cell type implicated in allergic disease pathology, are unknown. Therefore, we examined the effects of pimecrolimus on eosinophil superoxide anion production, degranulation and survival. Methods: Purified eosinophils from normal or atopic donors were incubated with serial dilutions of pimecrolimus (μM to nM) and then stimulated with platelet activating factor (PAF), interleukin 5 (IL5), secretory immunoglobulin A (sIgA) or Alternaria alternata (Alt) fungus extract. Eosinophil activation was monitored by cytochrome c reduction resulting from superoxide anion production and by a 2-site immunoassay for eosinophil-derived neurotoxin (EDN) in cellular supernatants, as a marker of degranulation. Eosinophil survival was measured by propidium iodide exclusion using flow cytometry after 4 days in culture. Results: Normal and atopic eosinophil superoxide anion production induced by PAF, and associated with increased intracellular calcium, was inhibited up to 37{\%} with 1 μM pimecrolimus. However, superoxide anion production induced by IL5 and sIgA was not consistently inhibited. EDN release, which ultimately depends on calcium, was inhibited about 30{\%} with PAF, IL5 and sIgA stimulation for normal and atopic donor eosinophils. Furthermore, calcium-dependent Alt-induced EDN release was inhibited up to 49{\%} with nanomolar pimecrolimus. Finally, increased eosinophil survival promoted by IL5 and sIgA was not influenced by pimecrolimus. Conclusion: Pimecrolimus moderately inhibits eosinophil superoxide anion production and EDN release associated with calcium mobilization, which may contribute to its efficacy in treating atopic dermatitis.",
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