The thiol proteinase inhibitors improve the abnormal rapid down-regulation of protein kinase C and the impaired natural killer cell activity in (Chediak-Higashi syndrome) beige mouse

Abnormal down-regulation of PKC is responsible for giant granule formation in fibroblasts from CHS (beige) mice—a thiol proteinase inhibitor, E-64-d, prevents giant granule formation in beige fibroblasts

“…Although A-SMase is known to be activated by diacylglycerol [26], the real mechanism by which SMases are activated is unknown. We had shown that E-64 eliminates the calpain-mediated PKC breakdown in murine PMNs and NK cells [10,11]. E-64-d is a cell-permeable and potent inhibitor of thiol proteinases including calpain [27].…”

“…Because we have previously reported that the membrane-bound PKC activity was rapidly down-regulated by PMA stimulation in PMNs and NK cells [9,10], we examined whether the abnormality in PKC activity would occur in fibroblasts from beige mice. In unstimulated cells, the PKC activity in beige fibroblasts was lower than that in normal fibroblasts, both in the cytosolic and the membrane-bound fractions (Fig.…”

“…The abnormal PKC down-regulation is eliminated by the treatment of cells with inhibitors of calpain, which is a thiol proteinase and proteolyzes PKC to an inactive form [9], and in addition, calpain inhibitors correct the abnormalities in concanavalin A (Con A)-induced cap formation and NK activity in beige mice [10,11]. It is well known that the lysosomal enzyme activity of elastase and cathepsin G is selectively decreased in PMNs from beige mice [12,13].…”

“…We have previously reported that the abnormally rapid down-regulation of protein kinase C (PKC) activity in polymorphonuclear leukocytes (PMNs) and natural killer (NK) cells from beige mice is responsible for the impaired immune functions [9,10]. The abnormal PKC down-regulation is eliminated by the treatment of cells with inhibitors of calpain, which is a thiol proteinase and proteolyzes PKC to an inactive form [9], and in addition, calpain inhibitors correct the abnormalities in concanavalin A (Con A)-induced cap formation and NK activity in beige mice [10,11].…”

Improvement of deficient natural killer activity and delayed bactericidal activity by a thiol proteinase inhibitor, E-64-d, in leukocytes from Chediak–Higashi syndrome patients in vitro

“…We previously reported that protein kinase C (PKC) activity is abnormally down-regulated after stimulation with phorbol ester or concanavalin A (Con A) in polymorphonuclear leukocytes (PMNs), NK cells, and fibroblasts from beige mice [10][11][12]. This aberrant downregulation of PKC was caused by the enhanced calpain-mediated proteolysis of PKC, and was shown to be responsible for the impaired cellular functions observed in CHS patients.…”