TY - JOUR
T1 - Effect of a thiol proteinase inhibitor, E-64-d, on susceptibility to infection with Staphylococcus aureus in Chediak-Higashi syndrome (beige) mice
AU - Morimoto, Michiko
AU - Tanabe, Fuminori
AU - Kasai, Hirotake
AU - Ito, Masahiko
N1 - Funding Information:
This work was supported in part by a grant from Taisho Pharmaceutical Co. (Saitama, Japan).
PY - 2007/7
Y1 - 2007/7
N2 - 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.
AB - 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.
KW - Chediak-Higashi syndrome
KW - bacterial infection
KW - beige mice
KW - calpain
KW - protein kinase C
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U2 - 10.1016/j.intimp.2007.03.004
DO - 10.1016/j.intimp.2007.03.004
M3 - Article
C2 - 17499200
AN - SCOPUS:34247891585
VL - 7
SP - 973
EP - 980
JO - International Immunopharmacology
JF - International Immunopharmacology
SN - 1567-5769
IS - 7
ER -