Increased interleukin-1alpha and interleukin-1beta production by macrophages of low-density lipoprotein receptor knock-out mice stimulated with lipopolysaccharide is CD11c/CD18-receptor mediated.
Immune mechanisms, including production of pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumour necrosis factor (TNF), play an important role in early atherogenesis. The study of the mechanisms responsible for the increased cytokine production capacity of hypercholesterolemic hosts is therefore crucial for finding new strategies aimed to stop the development of atherosclerosis. We assessed the lipopolysaccharide (LPS)-induced cytokine production of macrophages from low-density lipoproteins (LDL)-receptor knock-out (LDLR-/-) mice, which have a seven- to ninefold higher plasma LDL concentration. Macrophages of LDLR-/- mice produced approximately twofold more IL-1alpha and IL-1beta in response to LPS when compared with macrophages of control mice (LDLR+/+). TNF-alpha synthesis was only slightly increased. Removal of CD14 by phospholipase C treatment of cells decreased cytokine production by 50% (IL-1) to 80% (TNF), but the differences between LDLR-/- and LDLR+/+ remained the same. In contrast, treatment of cells with anti-CD11c monoclonal antibody inhibited the IL-1alpha and IL-1beta production in LDLR-/- mice towards normal values, while no effect could be seen on TNF. In conclusion, LDLR-/- macrophages stimulated with LPS synthesize more IL-1alpha and IL-1beta than controls and this phenomenon is mediated by the CD11c/CD18 receptor.
Netea
M G
MG
Division of General Internal Medicine, Department of Medicine, University Hospital Nijmegen, The Netherlands.
Demacker
P N
PN
Kullberg
B J
BJ
Boerman
O C
OC
Verschueren
I
I
Stalenhoef
A F
AF
Van Der Meer
J W
JW
D000818:Animals; D001667:Binding, Competitive; D018929:Cell Culture Techniques; D002462:Cell Membrane / Q000276:immunology; D015870:Gene Expression; D016167:Integrin alphaXbeta2 / Q000276:immunology*; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D008050:Lipid A / Q000276:immunology; D008055:Lipids / Q000097:blood; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000276:immunology*
D016167:Integrin alphaXbeta2; D007375:Interleukin-1; D008050:Lipid A; D008055:Lipids; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011973:Receptors, LDL