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 > or =500 s-1) of wild-type (WT) C57Bl/6, lymphocyte-deficient [recombinase-activating gene knockout (RAG1-/-)], and IL-12-deficient (p35-/- and p40-/-; 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-/--HC mice received splenocytes from WT-HC (WT --> RAG1-/-), p35-/--HC (p35-/- --> RAG1-/-), or p40-/--HC (p40-/- --> RAG1-/-) 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-/--ND, p35-/--ND, and p40-/--ND groups. Hypercholesterolemia-induced leukocyte adherence and emigration were attenuated in RAG1-/--HC vs. WT-HC mice but were similar to ND mice. Furthermore, compared with WT-HC animals, p35-/--HC and p40-/--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-/- mice were similar to responses of WT-HC mice. However, p35-/- --> RAG1-/- mice had lower levels of adherence and emigration vs. the WT --> RAG1-/- and WT-HC groups. Elevated levels of leukocyte adherence and emigration were restored by approximately 50% toward WT-HC levels in p40-/- --> RAG1-/- mice. These findings implicate IL-12 in the inflammatory responses observed in the venules of hypercholesterolemic mice.
Stokes
Karen Y
KY
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, 1501 E. Kings Highway, Shreveport, LA 71130-3932, USA.
Clanton
E Chris
EC
Gehrig
John L
JL
Granger
D Neil
DN
D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics; D006937:Hypercholesterolemia / Q000276:immunology* / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology*; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000276:immunology; D014657:Vasculitis / Q000276:immunology* / Q000378:metabolism
D018398:Homeodomain Proteins; C064658:RAG-1 protein; D018664:Interleukin-12; D002784:Cholesterol