Role of interleukin 12 in hypercholesterolemia-induced inflammation

We have previously shown that T lymphocytes and interferon-[gamma] are involved in hypercholesterolemia-induced leukocyte adhesion to vascular endothelium. This study assessed the contribution of interleukin 12 (IL-12) to these hypercholesterolemia-induced inflammatory responses. Intravital videomicroscopy was used to quantify leukocyte adhesion and emigration and oxidant stress (dihydrorhodamine oxidation) in unstimulated cremasteric venules (wall shear rate [greater than or equal to] 500 [s.sup.-1]) of wild-type (WT) C57B1/6, lymphocyte-deficient [recombinase-activating gene knockout ([RAG1.sup.-/-])], and IL-12-deficient ([p35.sup.-/-] and [p40.sup.-/-]; p35 and p40 are the two subunits of active IL-12) mice on either a normal (ND) or high-cholesterol (HC) diet for 2 wk. [RAG1.sup.-/-]-HC mice received splenocytes from WT-HC (WT [right arrow] [RAG1.sup.-/-]), [p35.sup.-/-]-HC ([p35.sup.-/-] [right arrow] [RAG1.sup.-/-]), or [p40.sup.-/-]-HC ([p40.sup.-/-] [right arrow] [RAG1.sup.-/-]) mice. Compared with WT-ND mice, WT-HC mice exhibited exaggerated leukocyte adherence and emigration as well as increased dihydrorhodamine oxidation. The enhanced leukocyte recruitment was absent in the [RAG1.sup.-/-]-ND, [p35.sup.-/-]-ND, and [p40.sup.-/-]-ND groups. Hypercholesterolemia-induced leukocyte adherence and emigration were attenuated in [RAG1.sup.-/-]-HC vs. WT-HC mice but were similar to ND mice. Furthermore, compared with WT-HC animals, [p35.sup.-/-]-HC and [p40.sup.-/-]-HC mice showed significantly lower leukocyte adhesion and tissue oxidant stress responses, but these values were comparable to ND mice. Leukocyte adherence and emigration in WT [right arrow] [RAG1.sup.-/-] mice were similar to responses of WT-HC mice. However, [p35.sup.-/-] [right arrow] [RAG1.sup.-/-] mice had lower levels of adherence and emigration vs. the WT [right arrow] [RAG1.sup.-/-] and WT-HC groups. Elevated levels of leukocyte adherence and emigration were restored by ~50% toward WT-HC levels in [p40.sup.-/-] [right arrow] [RAG1.sup.-/-] mice. These findings implicate IL-12 in the inflammatory responses observed in the venules of hypercholesterolemic mice. endothelium; oxidative stress; lymphocytes