By using a strategy that we have developed to search for the ligands of orphan seven-transmembrane-domain receptors [S. Hinuma et al., Nature 393 (1998) 272-276], we have recently identified a natural ligand, apelin, for the orphan 7TMR, APJ [K. Tatemoto et al., Biochem. Biophys. Res. Commun. 251 (1998) 471-476]. In this paper, we isolated rat and mouse apelin cDNAs, and analyzed the tissue distribution of apelin mRNA in rats. Although apelin mRNA was widely detected in a variety of tissues, the highest expression of apelin mRNA was detected in the mammary gland of pregnant rats. In the mammary gland, biologically active apelin and its mRNA considerably increased during pregnancy and lactation, and reached a maximal level around parturition. Moreover, a large amount of apelin (14-93 pmol/ml) was found to be secreted in the bovine colostrum, and it was still detectable even in commercial bovine milk. Since apelin partially suppressed cytokine production by mouse spleen cells in response to T cell receptor/CD3 cross-linking, the oral intake of apelin in the colostrum and milk might modulate immune responses in neonates.

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Heat-killed Lactobacillus plantarum strain L-137 (HK-LP) is a potent inducer of IL-12 in vitro as well as in vivo in mice. HK-LP has been shown to suppress IgE production against food allergens, as well as tumor growth in mice, through IL-12 production, which induces the T helper (Th) 1 type immune response. To determine whether the intake of HK-LP influences immune function and the quality of life (QOL), a randomized, double-blind, placebo-controlled, parallel study was conducted in healthy subjects. Sixty subjects (30 men and 30 women, mean age 56.3 y) were randomly assigned to receive a capsule containing 10 mg of HK-LP daily or a matching capsule for 12 wk. Biomarkers for innate immunity such as the natural killer activity of peripheral blood mononuclear cells, neutrophil phagocytosis, and cell surface expression of CD64 on monocytes were measured every 4 wk. Biomarkers for acquired immunity such as concanavalin A (Con A)-induced proliferation, percentages of INF-gamma and IL-4-producing cluster of differentiation (CD)4(+) T cells (Th1:Th2 ratio), and the serum IgG4:IgG ratio were measured every 4 wk or at wk 0 and wk 12. Health-related QOL was assessed using a self-rating questionnaire with 26 items. Among the measured biomarkers, the percent change in Con A-induced proliferation and the Th1:Th2 ratio in the HK-LP group was greater than those in the control group (P = 0.036 and P = 0.002, respectively). The degree of improvement in QOL was higher in the HK-LP group than in the control group at wk 8 (P = 0.049) and tended to be higher at wk 12 (P = 0.092). These results suggest that a daily intake of HK-LP augments acquired immunity, especially Th1-related immune functions in healthy subjects, thereby improving the health-related QOL.

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