Induction of cytokine tolerance in rodent hepatocytes by chylomicron-bound LPS is low-density lipoprotein receptor dependent.
We examined the role of lipoprotein receptors in mediating chylomicron-bound lipopolysaccharide (CM-LPS)-induced cytokine tolerance in rodent hepatocytes. We found that 2 h of pretreatment with CM-LPS (5 mg TG/mL) was sufficient to induce cytokine tolerance, as measured by decreased nitric oxide (NO) production by hepatocytes (20% of the Control group, P < 0.03). Tolerance was evident as early as 2 h after pretreatment and disappeared after 40 h. Furthermore, we evaluated the roles of the low-density lipoprotein (LDL) receptor (LDLR) and LDL receptor-related protein (LRP) in the induction of cytokine tolerance in hepatocytes. Biochemical inhibition of the receptors or use of hepatocytes from LDLR-deficient mice revealed that functional LDLR was necessary for the induction of tolerance. However, by increasing the pretreatment time, the LRP compensated for the absence of the LDLR in induction of cytokine tolerance. In conclusion, CM-LPS-mediated induction of cytokine tolerance to proinflammatory cytokines is a time- and dose-dependent process that requires functional lipoprotein receptors. These findings underscore an interrelationship between TG-rich lipoprotein metabolism and innate immunity.
Kasravi
F Behzad
FB
University of California at San Francisco Surgical Research Laboratory at San Francisco General Hospital, University of California, San Francisco, California 94110, USA.
Welch
William J
WJ
Peters-Lideu
Clare A
CA
Weisgraber
Karl H
KH
Harris
Hobart W
HW
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D002914:Chylomicrons / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000378:metabolism*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D002914:Chylomicrons; D016207:Cytokines; D008070:Lipopolysaccharides; D011973:Receptors, LDL; D014280:Triglycerides; D009569:Nitric Oxide