The effect of gamma-interferon to inhibit macrophage-high density lipoprotein interactions is reversed by 15-deoxy-delta12,14-prostaglandin J2.
Macrophage activation has been recognized as playing a central role in chronic inflammatory diseases in general and, more specifically, in the vascular wall during the progression of atherosclerotic lesions. Macrophage-activating factors present within the atherosclerotic lesion include the colony-stimulating factors and gamma interferon (IFNgamma). In the present study, the effects of IFNgamma on macrophage binding and uptake of fluorochrome-labeled high density lipoprotein (HDL) were investigated by flow cytometry and by measuring the amount of the type B scavenger receptors CD36 and scavenger receptor type B (SR-BI) by Northern blot analysis. IFNgamma-, but not granulocyte macrophage colony-stimulating factor (GM-CSF)-treated murine peritoneal macrophages displayed a two- to threefold decrease in Dil-labeled HDL uptake. This effect was observed in the absence of a comparable decrease in SR-BI message and protein or CD36 message. This decrease in both HDL binding and uptake was reversed by the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, 15-deoxy-delta12,4-prostaglandin J2 (15d-PGJ2), which also inhibited the IFNgamma induction of the beta2 integrin CD11a. Furthermore, 15d-PGJ2 increased the expression of SR-BI and CD36 message and SR-BI protein which was reflected in an increase in HDL binding and uptake. These results suggest a role for PPARgamma agonists in modulating the IFNgamma-mediated macrophage effector functions relevant to atherosclerotic disease progression.
Zuckerman
S H
SH
Division of Cardiovascular Research, Lilly Research Labs, Indianapolis, Indiana 46285, USA. Zuckerman_Steven@lilly.com
Panousis
C
C
Mizrahi
J
J
Evans
G
G
D000818:Animals; D001483:Base Sequence; D015342:DNA Probes; D007371:Interferon-gamma / Q000494:pharmacology*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D015342:DNA Probes; D008075:Lipoproteins, HDL; D007371:Interferon-gamma; D015230:Prostaglandin D2