Reduced inflammatory potential of peritoneal macrophages recruited in mice pretreated with a glycolipid synthesis inhibitor.
Integral components of mammalian cell membranes, glycosphingolipids (GSL) reside in specialized plasma membrane microdomains critical for cell signaling. N-alkylated nojirimycins are compounds developed for GSL substrate deprivation therapy, blocking GSL synthesis by specifically inhibiting an essential enzyme, ceramide glucosyltransferase. Peritoneal macrophages recruited in mice pretreated with an inhibitory N-alkylnojirimycin displayed a reduced capacity to release either TNFalpha or interleukin-6 when re-exposed to whole killed E. coli in vitro. Cell viability and protein content were not affected. A nojirimycin analogue without GSL inhibitory capacity had no effect. The results show inhibition of GSL synthesis in vivo by an N-alkylnojirimycin can reduce the response to an inflammatory stimulus and indicate N-alkylnojirimycins have experimental and potential clinical value for modulating innate immune responses in vivo.
Yohe
H C
HC
Research Service, Department of Veterans Affairs, VA RO & MC, 215 North Main Street, White River Junction, VT 05009, USA. herbert.c.yohe@dartmouth.edu
Kitzmiller
T J
TJ
Bement
W J
WJ
Dwyer
B E
BE
Sinclair
J F
JF
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005944:Glucosamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006028:Glycosphingolipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007113:Immunity, Innate / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H
D016207:Cytokines; D004791:Enzyme Inhibitors; D006028:Glycosphingolipids; D017485:1-Deoxynojirimycin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D005944:Glucosamine; C013626:nojirimycin