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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 (IFNγ). In the present study, the effects of IFNγ 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. IFNγ-, but not granulocyte macrophage colony-stimulating factor (GM-CSF)-treated murine peritoneal macrophages displayed a two- to threefold decrease in Dil-labeled HDI uptake. This effect was observed in the absence of a comparable decrease in SR-BI meassage and protein or CD36 message. This decrease in both HDL binding and uptake was reversed by the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, Δ12,14-prostaglandin J2 (15d-PGJ2), which also inhibited the IFNγ inductin of the β2 integrin CD1 1a. 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 PPARγ agonists in modulating the IFNγ-mediated macrophage effector functions relevant to atherosclerotic disease progression.