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We have previously shown that T lymphocytes and interferon-γ 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 ≥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 → RAG1[sup -/-]), p35[sup -/-]-HC (p35[sup -/-] → RAG1[sup -/-]), or p40[sup -/-]-HC (p40[sup -/-] → 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 → RAG1[sup -/-] mice were similar to responses of WT-HC mice. However, p35[sup -/-] → RAG1[sup -/-] mice had lower levels of adherence and emigration vs. the WT → RAG1[sup -/-] and WT-HC groups. Elevated levels of leukocyte adherence and emigration were restored by ∼50% toward WT-HC levels in p40[sup -/-] → RAG1[sup -/-] mice. These findings implicate IL-12 in the inflammatory responses observed in the venules of hypercholesterolemic mice. [ABSTRACT FROM AUTHOR]

OBJECTIVE:: Hypercholesterolemia promotes the adhesion of leukocytes to vascular endothelium in large and microscopic blood vessels. Lymphocytes that can modulate endothelial cell adhesion molecule expression have been implicated in the altered structure and function of large arterial vessels associated with chronic hypercholesterolemia. This study assesses the contribution of CD4+ and CD8+ T-cells to acute inflammatory responses observed in the microcirculation of hypercholesterolemic mice. METHODS:: Intravital microscopy was used to quantify baseline leukocyte–endothelial cell interactions in cremasteric postcapillary venules of wild-type (WT) and severe combined immunodeficient (SCID) mice placed on a normal (ND) or high-cholesterol (HC) diet for 2 weeks. A group of SCID-HC mice received splenocytes from WT-HC mice (WT→SCID). Separate WT-HC groups were depleted of neutrophils or CD4+ and/or CD8+ T-cells. RESULTS:: WT-HC mice, compared with WT-ND, exhibited exaggerated leukocyte adherence and emigration. These leukocytes were predominantly granulocytes. These responses were absent in neutropenic WT-HC mice. SCID-HC mice also showed significantly less leukocyte adherence and emigration than WT-HC mice. Elevated leukocyte adherence and emigration were restored in WT→SCID mice, despite a continued absence of circulating blood lymphocytes. Selective depletion of either CD4+ or CD8+ cell populations attenuated HC-induced leukocyte adhesion but not emigration. However, simultaneous depletion of both CD4+ and CD8+ cells attenuated both leukocyte adhesion and emigration to ND levels. DISCUSSION:: These findings indicate that both CD4+ and CD8+ T-cells contribute to granulocyte adhesion and emigration elicited in postcapillary venules by hypercholesterolemia.Microcirculation (2002) 9, 407–417. doi:10.1038/sj.mn.7800148 [ABSTRACT FROM AUTHOR]