High glucose concentrations impair the activation of K+ channels and proteases in undifferentiated THP-1 monocytes.
Transient alkalization caused by activation of the BK(Ca) channels has been reported to be essential for the activation of proteolytic enzymes and bacterial killing in the leukocytic phagosomes. We investigated the effects of high glucose concentrations on these processes in THP-1 cells. While E. coli transiently raised the pH of the phagosomes in THP-1 monocytes, high glucose concentrations impaired the transient rise of pH in a dose-and time-dependent manner. Electrophysiological studies confirmed that the bacteria elicited a transient K+ current, and that a high glucose concentration diminished the current. High glucose concentrations also inhibited the activation of cathepsin G in the THP-1 cells. NS1619, a BK(Ca) channel opener, accentuated the transient alkalization induced by the bacteria, and reversed the inhibitory effect of high concentrations of glucose. However, electrophysiological study revealed that the membrane current differed from the BK(Ca) current. Our findings indicate that high glucose concentrations impair K+ channel activation and the subsequent activation of proteolytic enzymes in THP-1 monocytes. The precise identity of the K+ channel remains unclear, although it dose not appear to be the BK(Ca). Suppression of the transient alkalization and activation of proteases may be one of the mechanisms for bacterial killing by phagocytes in diabetic patients.
Department of Geriatrics and Vascular Medicine, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Hiroshi
H
Asaoka
Junko
J
Kurokawa
Tetsushi
T
Furukawa
Kentaro
K
Shimokado
D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D004926:Escherichia coli; D005947:Glucose / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006943:Hyperglycemia / Q000276:immunology*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology*; D010588:Phagosomes / Q000276:immunology*; D024681:Potassium Channels, Calcium-Activated / Q000276:immunology*; D012697:Serine Endopeptidases; D018417:Th1 Cells / Q000201:enzymology*
D024681:Potassium Channels, Calcium-Activated; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; D005947:Glucose