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.
Protein kinase C (PKC) is essential in intracellular signal transduction for various cell functions including natural killer (NK) cell activity. This enzyme is hydrolysed by calpain, which is Ca2+-dependent thiol proteinase. We showed here that in NK activity-deficient beige (bg/bg) mouse, the model of Chediak-Higashi syndrome, the translocated membrane-bound PKC activity declined rapidly in NK cell-enriched lymphocytes after TPA stimulation. However, the rapid decline was abolished by the pretreatment of cells with leupeptin (a thiol and serine proteinase inhibitor) or E64 (a thiol proteinase inhibitor). Furthermore, these reagents improved the impaired NK cell activity in beige mouse whereas they did not affect NK cell activity in C57BL/6 (+/+) and the heterozygous (+/bg) mice. Meanwhile, TPA stimulation induced only low levels in NK cytotoxic factors (NKCF) release from beige NK cells, but these reagents augmented the lowered NKCF release. These results suggest that the improvement of impaired NK cell activity in beige mouse by the thiol proteinase inhibitors may be due to the elimination of abnormal rapid down-regulation of PKC, resulting in the augmentation of the lowered PKC activity.
Ito
M
M
Department of Bacteriology, Fukushima Medical College, Japan.
Sato
A
A
Tanabe
F
F
Ishida
E
E
Takami
Y
Y
Shigeta
S
S
D000818:Animals; D002154:Calpain / Q000378:metabolism; D002609:Chediak-Higashi Syndrome / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D004195:Disease Models, Animal; D007694:Killer Cells, Natural / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D055646:Killer Factors, Yeast; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D015853:Cysteine Proteinase Inhibitors; D055646:Killer Factors, Yeast; D007976:Leupeptins; D011506:Proteins; C034323:EP 459; D011493:Protein Kinase C; D002154:Calpain; D007930:Leucine; C032854:leupeptin; D013755:Tetradecanoylphorbol Acetate