The Role of Interleukin 12 in the Development of Atherosclerosis in ApoE-Deficient Mice

Abstract

Abstract-The cytokine profile of atherosclerotic aortas from apoE-deficient mice was assessed by reverse transcriptasepolymerase chain reaction. The results clearly showed that the expression of mRNA for IL-12p40 was evident in aortas from 3-month-old apoE-deficient mice. The mRNA for IL-10 was detected in aorta from these mice at the age of 6 months, indicating that expression of IL-12 is earlier than that of IL-10 in these animals. Concurrent with IL-12p40, the mRNA for the T-cell cytokine IFN-␥, but not IL-4, was detected in aortas of mice at young and old ages. Both in situ hybridization and immunostaining further demonstrated the localization of IL-12 in macrophages of atherosclerotic lesions. Immunohistochemistry also demonstrated the expression of costimulatory molecules B7-1 and B7-2 in macrophages, suggesting that activation of T lymphocytes by macrophages may occur via surface antigens in lesions. When the immunoglobulin isotype of the antioxidized LDL antibodies in sera of apoE-deficient mice was determined, it revealed that both IgM and IgG were present. Furthermore, IgG2a is predominant and comprises Ϸ50% of the antioxidized LDL IgG in sera from young mice (3 months), but decreased to lower levels (35%) in older mice (6 months). Daily administration of IL-12 led to an increase in serum levels of antioxidized LDL antibodies and accelerated atherosclerosis in young apoE-deficient mice compared with control mice injected with PBS alone. Taken together, these data suggest that IL-12 plays an active role in regulating the immune response during the early phase of atherosclerosis in apoE-deficient mice.

Lymphocytes are important in early atherosclerosis

“…In contrast, Th2 cells, which antagonize Th1 function (7), may serve to impede the development of atherosclerotic lesions. Consistent with this notion, IL-12, a potent Th1 inducer, has been shown to promote atherogenesis (45,48). In contrast, IL-10, a potent Th2 cytokine, has been shown to antagonize atherogenesis (46)(47)(48)(49).…”

“…The development of murine models has provided an opportunity to evaluate the potential role of these immune cells in disease pathogenesis (12). Recent studies in mice have demonstrated that macrophages and two T cell activators, CD40 and IL-12, effectively promote atherogenesis (13,21,45); and that IL-10, a known T cell antagonist, appears to moderate atherogenesis (46)(47)(48)(49). Moreover, IFN-γ, a potent proinflammatory T cell effector, has also been shown to promote atherogenesis (2,5,22).…”

“…2, 22-25, 29) and antiatherogenic activities (e.g., IL-10-secreting TH2 cells; refs. 45,[47][48][49]. There may also be inherent differences between collagen accumulation in the apoE knockout model (exploited in earlier studies; refs.…”

IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis

“…Specifically, adaptive responses to OxLDL have been shown to increase during disease progression, but their exact role in atherogenesis is uncertain (18,19). Notably, in cholesterol-fed apoE -/-mice, advanced stages of atherosclerosis are associated with increased accumulation of OxLDL (20), and in this setting there is an immune deviation of OxLDL-specific Th1 responses toward Th2 (21,22). The Th2 cytokine IL-4 has been reported to have either pro-or anti-atherogenic effects (23)(24)(25), whereas IL-10 secretion by T cells decreases atherogenesis (26,27).…”

Apoptose et syndromes coronariens aigus

“…En outre, la quantité d'interleukine (IL)-18, un inducteur de la production d'IFN-γ présent dans les plaques carotides humaines, est positivement corrélée à l'instabilité clinique (présence d'accident vasculaire céré-bral) et anatomique (présence d'ulcération) de la lésion [10]. L'injection à des souris apoE -/-d'IL-18 ou d'IL-12, une autre cytokine pro-inflammatoire néces-saire à l'induction de la production d'IFN-γ, augmente significativement la taille des plaques, qui deviennent alors très riches en cellules inflammatoires et présen-tent un phénotype instable [9,11]. D'autres voies inflammatoires, comme celle impliquant l'interaction entre le récepteur CD40 et son ligand, sont également importantes pour la progression et l'instabilité des plaques [12].…”