Yukihito Nakai

Allograft inflammatory factor-1 regulates trinitrobenzene sulphonic acid-induced colitis

The expression of allograft inflammatory factor‐1 (AIF‐1) in 2,4,6‐trinitrobenzene sulphonic acid (TNBS)‐induced colitis, a model for T helper 1 (Th1) type disease, was investigated in BALB/c mice. The AIF‐1 expression was significantly increased in the colitis lesion compared to that in the normal colon. We then prepared AIF‐1 transgenic mice (Tgm) with the BALB/c background that express high levels of AIF‐1 in lymphoid tissues and the colon. When AIF‐1 Tgm were administrated TNBS, the TNBS‐induced colitis was ameliorated compared with that in non‐transgenic littermates. The amelioration of colitis was associated with the low expression of interleukin‐1β in the colon. The present findings suggest that AIF‐1 regulates Th1‐type inflammatory responses.

Natural killer T cells are required for lipopolysaccharide-mediated enhancement of atherosclerosis in apolipoprotein E-deficient mice

Lipopolysaccharide (LPS) has been shown to accelerate atherosclerosis and to increase the prevalence of IL-4-producing natural killer T (NKT) cells in various tissues. However, the role of NKT cells in the development of LPS-induced atherosclerotic lesions has not been fully tested in NKT cell-deficient mice. Here, we examined the lesion development in apolipoprotein E knockout (apoE-KO) mice and apoE-KO mice on an NKT cell-deficient, CD1d knockout (CD1d-KO) background (apoE-CD1d double knockout; DKO). LPS (0.5 μg/g body weight/wk) or phosphate-buffered saline (PBS) was intraperitoneally administered to apoE-KO and DKO mice (8-wk old) for 5 wk and atherosclerotic lesion areas were quantified thereafter. Consistent with prior reports, NKT cell-deficient DKO mice showed milder atherosclerotic lesions than apoE-KO mice. Notably, LPS administration significantly increased the lesion size in apoE-KO, but not in DKO mice, compared to PBS controls. Our findings suggest that LPS, and possibly LPS-producing bacteria, aggravate the development of atherosclerosis primarily through NKT cell activation and subsequent collaboration with NK cells.

Lower prevalence of circulating natural killer T cells in patients with angina : a potential novel marker for coronary artery disease

ObjectiveAtherosclerosis is an inflammatory disease. Natural killer T cells are a unique lymphocyte subset that can recognize lipid antigens presented by CD1d and secrete copious amounts of pro-atherogenic cytokines such as interferon-&ggr;. We have previously shown that natural killer T cells accelerate atherosclerosis in mice and macrophages incubated with oxidized low-density lipoproteins induce natural killer T cells to produce interferon-&ggr;. Thus, whether the prevalence of natural killer T cells in peripheral blood is altered in patients with angina pectoris and its correlation with coronary risk factors was determined. MethodCell profiling was performed using flow cytometry in patients with stable angina, unstable angina (Braunwald IIIB), and healthy controls. Natural killer T cells in peripheral blood were identified by the expression of natural killer T specific invariant T cell receptor &agr;-chain (V&agr;24) and T cell receptor &bgr;-chain (V&bgr;11). ResultsPrevalence of natural killer T (V&agr;24–V&bgr;11 double positive) cells was significantly decreased in patients with unstable angina and stable angina compared with that in controls. No significant differences were observed in the prevalence between unstable and stable angina. Reduction of natural killer T cells was independently associated with the presence of angina. ConclusionsLower prevalence of circulating natural killer T cells is related to the presence of coronary artery disease. As T cell receptor down-regulation or apoptosis after natural killer T cell activation and subsequent interferon-&ggr; release may contribute to atherogenesis, natural killer T cells can become a novel therapeutic target for the prevention and treatment of atherosclerotic vascular diseases.

Intracellular signal transduction modulating expression of plasminogen activator inhibitor-1 in adipocytes.

The concentrations in blood of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis and proteolysis, are elevated in obese and insulin-resistant subjects, predispose them to the risk of thrombosis, and may accelerate atherogenesis. Adipose tissue is a prominent source. Accordingly, intracellular signaling pathways that may influence PAI-1 expression in adipocytes have been the focus of considerable study. Rho, a small GTP binding and GTPase protein, when activated in turn activates its target, Rho-associated coiled-coil forming protein, to yield an active kinase, Rho-kinase, an effector in the Rho pathway. Rho-kinase exerts calcium-sensitizing effects in vascular smooth muscle cells and inhibitory effects on transforming growth factor-beta (TGF-beta) expression in chicken embryonic heart cells. Because TGF-beta is a powerful agonist of PAI-1 expression, we characterized the effects of inhibition of Rho-kinase in 3T3-L1 adipocytes. PAI-1 mRNA was determined by Northern blotting, and PAI-1 protein was determined by Western blotting. The Rho-kinase inhibitor, Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide], increased PAI-1 expression markedly. Although genistein, a flavonoid tyrosine kinase, attenuated the increase of PAI-1 induced by Y-27632, other non-flavonoid tyrosine kinase inhibitors did not. However, another flavonoid, daidzein, which lacks tyrosine kinase activity, decreased basal PAI-1 expression and attenuated the induction of PAI-1 expression by Y-27632. Thus, the Rho/Rho-kinase system inhibits PAI-1 expression by a flavonoid-sensitive mechanism in adipocytes. Therefore, flavonoids may be useful in decreasing elevated PAI-1 expression in adipose tissue and its consequent pathophysiologic sequelae.