Effect of a thiol proteinase inhibitor, E-64-d, on susceptibility to infection with Staphylococcus aureus in Chediak-Higashi syndrome (beige) mice

Michiko Morimoto, Fuminori Tanabe, Hirotake Kasai, Masahiko Ito

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

We previously reported that abnormally down-regulated protein kinase C (PKC) activity is responsible for the impaired cellular function of natural killer cells and polymorphonuclear cells (PMNs), and the giant granule formation in fibroblasts in the beige mouse, an animal model of Chediak-Higashi syndrome. Here, we examine the effect of oral or intraperitoneal administration of E-64-d, which protects PKC from calpain-mediated proteolysis, on the impaired cellular function in PMNs from beige mice. We found that oral administration of E-64-d (12.5 mg/kg body weight per day) for three consecutive days, significantly improved the abnormally increased concanavalin A (Con A) cap formation and the decreased lysosomal enzyme activity in beige PMNs. In addition, E-64-d significantly improved the delayed bactericidal activity against Staphylococcus aureus. In contrast, E-64-d at the same dose did not affect these cellular functions in PMNs from C57BL/6J mice. We confirmed that the abnormal down-regulation of PKC after Con A stimulation was eliminated in PMNs from E-64-d-treated beige PMNs. We then examined whether the administration of E-64-d to beige mice improved the susceptibility to experimental infection with S. aureus (2 × 108/mouse). Both intraperitoneal and oral administration of E-64-d to beige mice resulted in a significant increase in survival, whereas E-64-d at the same dose did not alter the survival rate in normal mice. These results suggest that the administration of E-64-d may be effective against severe bacterial infection in Chediak-Higashi syndrome.

Original languageEnglish
Pages (from-to)973-980
Number of pages8
JournalInternational Immunopharmacology
Volume7
Issue number7
DOIs
Publication statusPublished - Jul 2007
Externally publishedYes

Keywords

  • bacterial infection
  • beige mice
  • calpain
  • Chediak-Higashi syndrome
  • protein kinase C

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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