The novel cytokine interferon-gamma-inducing factor (IGIF) augments natural killer (NK) cell activity in cultures of human peripheral blood mononuclear cells (PBMC), similarly to the structurally unrelated cytokine interleukin (IL)-12. IGIF has been found to enhance the production of interferon-gamma (IFN-gamma) and granulocyte/macrophage colony-stimulating factor (GM-CSF) while inhibiting the production of IL-10 in concanavalin A (Con A)-stimulated PBMC. In this study, when anti-CD3 monoclonal antibody (mAb)-stimulated human enriched T cells were exposed to IGIF, the cytokine dose-dependently enhanced the proliferation of the cells and this could be completely inhibited by a neutralizing antibody against IL-2 at lower concentrations of IGIF. Neutralizing antibody against IFN-gamma had only insignificant inhibitory effects on T cell proliferation at higher concentrations of IGIF. Enzyme-linked immunosorbent assays (ELISA) revealed that, like PBMC, T cells exposed to IGIF produced large amounts of IFN-gamma; however, changes in the production of IL-4 and IL-10 were minimal. IGIF, but not IL-12, significantly enhanced IL-2 and GM-CSF production in T cell cultures, as determined by CTLL-2 bioassay and ELISA, respectively; however, both IGIF and IL-12 enhanced IFN-gamma production by the T cells. When T cells were exposed to a combination of IGIF and IL-12, a synergistic effect was observed on the production of IFN-gamma, but not on production of IL-2 and GM-CSF. In conclusion, IGIF enhances T cell proliferation apparently through an IL-2-dependent pathway and enhances Th1 cytokine production in vitro and exhibits synergism when combined with IL-12 in terms of enhanced IFN-gamma production but not IL-2 and GM-CSF production. Based on structural and functional differences from any known cytokines, it was recently proposed that this cytokine be designated interleukin-18.

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Administration of monoclonal anti-CD3 antibody to mice treated with Propionibacterium acnes induced secretion of a high level of gamma interferon (IFN-␥) into the circulation system, while it induced no significant release in untreated mice. In order to analyze this high-level induction of IFN-␥ in these bacterium-treated mice, we investigated the factors that might be involved. An activity that induces IFN-␥ in T cells was observed in the liver extracts of mice treated with P. acnes and subsequently challenged with lipopolysaccharide. Here, we purified an IFN-␥-inducing factor from the liver extract to homogeneity and characterized it. Its molecular mass was 18 to 19 kDa, and its pI was 4.9. The amino acid sequence of the NH 2-terminal portion was determined and shown to have no similarities to any protein in the EMBL, GenBank, and PIR data bases. The same molecule was also demonstrated in the serum factor that was previously reported to have an IFN-␥inducing activity and to have an apparent molecular mass of 75 kDa. Moreover, the activity of this serum factor was recovered in the fraction containing the 18-to 19-kDa protein under reducing conditions and was shown to have the same NH 2-terminal amino acid sequence as that of the factor from the liver extract. In addition to the ability to induce IFN-␥, this protein augmented T-cell proliferation and NK activity in the spleen cells. Thus, several of its biological activities were apparently similar to those of interleukin-12. These results indicated that this novel protein, which exhibited marked costimulatory activity on IFN-␥ production in vitro, was elevated in vivo in response to P. acnes treatment. This factor, probably released from the producing cells by lipopolysaccharide stimuli, may be involved in the high-level induction of IFN-␥ in the P. acnes-treated mice. Recently CD4 ϩ T (Th) cells were divided into distinct subsets according to the profiles of cytokine production (15, 22, 23, 25). This will help our understanding of the regulatory mechanism of immune responses caused by infections with a variety of pathogens. Accessory cells or cytokines produced in response to the initial contact with antigens were shown to exhibit important functions in the development of these cells, depending on the antigenic characteristics. Cells of the Th2 subset are thought to require interleukin-1 (IL-1) or IL-4 for their development (6, 9, 11, 12, 24), and it is shown that IL-12 induces the differentiation of Th1 cells from uncommitted T cells (7, 13, 21). Gamma interferon (IFN-␥), which is produced by activated CD4 ϩ T (Th1), CD8 ϩ T, or NK cells, has been demonstrated to play important roles in cell-mediated immunity. Each of these producer cells may be regulated in the same or different manners, when stimulated. IL-2 was shown to induce IFN-␥ production in NK cells (3, 8), and IL-12 was demonstrated to be involved in IFN-␥ induction in CD4 ϩ T cells or NK cells (7, 13, 21). However, the detailed mechanisms underlying IFN-␥ production as well as the mechanism of devel...

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SummaryOur previous study has shown that a soluble hesperidin derivative, glucosyl hesperidin (G-hesperidin), preferentially lowers serum triglyceride (TG) level in hypertriglyceridemic subjects through the improvement of very low-density lipoprotein (VLDL) metabolic abnormality. G-Hesperidin has also been found to decrease an elevated serum apolipoprotein B (apo B) level in the hypertriglyceridemic subjects, suggesting a possibility that this compound suppresses excess VLDL secretion in the liver. In the present study, to gain a better understanding of possible mechanisms by which G-hesperidin lowers serum TG, we examined whether this derivative affects apo B secretion from HepG2 human hepatoma cells, a model of hepatic VLDL secretion. As a result, G-hesperidin significantly reduced apo B secretion from the oleate-stimulated HepG2 cells. Furthermore, G-hesperidin significantly suppressed apo B secretion only in the oleate-stimulated cells and failed to act on the cells incubated without oleate. In the oleate-stimulated cells, G-hesperidin significantly decreased cellular cholesteryl ester (CE), although it had no effect on cellular TG or free cholesterol amounts. Moreover, the oleate-stimulated cells had a decrease in cellular apo B amounts by G-hesperidin exposure. These findings indicate that G-hesperidin downregulates the assembly of apo B-containing lipoproteins via the reduction of CE synthesis augmented with oleate and results in suppressing excess apo B secretion from the cells. This effect is speculated to be associated with the improvement of VLDL metabolic abnormality in hypertriglyceridemic subjects and considered as a mechanism of lowering serum TG. Key Words glucosyl hesperidin, very low-density lipoprotein, apolipoprotein B, cholesteryl ester, HepG2 cells Hesperidin, a citrus flavonoid, is well known to decrease capillary fragility and permeability ( 1 ). This compound has also been reported to have various physiological activities including antioxidant effect ( 1 ), antihypertensive effect ( 2 ) and antiallergic effect ( 3 ). Therefore, hesperidin has attracted attention as a multifunctional food ingredient. However, the use of this flavonoid in the field of foods has been limited because of its low water solubility.To solve this problem, Hijiya and Miyake have synthesized a soluble derivative of hesperidin, glucosyl hesperidin (G-hesperidin), by regioselective transglycosylation with cyclodextrin glucanotransferase from Bacillus stearothermophilus (Fig. 1) ( 4 ). G-Hesperidin is very soluble in water, and its solubility is about 10,000 times greater than that of conventional hesperidin ( 4 ). Moreover, it has been verified that this derivative releases hesperidin through hydrolysis by brush border ␣ -glucosidases ( 4 , 5 ). Our recent studies have shown that Ghesperidin as well as hesperidin exhibits such physiological activities as decrease of serum lipid peroxide level in hyperlipidemic mice ( 6 ), antihypertensive effect on spontaneously hypertensive rats ( 7 , 8 ) and suppression of passive ...