A successful pregnancy depends on a complex process that establishes fetomaternal tolerance. Seminal plasma is known to induce maternal immune tolerance to paternal alloantigens, but the seminal factors that regulate maternal immunity have yet to be characterized. Here, we show that a soluble form of CD38 (sCD38) released from seminal vesicles to the seminal plasma plays a crucial role in inducing tolerogenic dendritic cells and CD4+ forkhead box P3 + (Foxp3 + ) regulatory T cells (Tregs), thereby enhancing maternal immune tolerance and protecting the semiallogeneic fetus from resorption. The abortion rate in BALB/c females mated with C57BL/6 Cd38 −/− males was high compared with that in females mated with Cd38 +/+ males, and this was associated with a reduced proportion of Tregs within the CD4 + T-cell pool. Direct intravaginal injection of sCD38 to CBA/J pregnant mice at preimplantation increased Tregs and pregnancy rates in mice under abortive sonic stress from 48 h after mating until euthanasia. Thus, sCD38 released from seminal vesicles to the seminal plasma acts as an immunoregulatory factor to protect semiallogeneic fetuses from maternal immune responses.eventy-five percent of pregnancies that are lost represent failure of implantation and are therefore not clinically recognized as pregnancies (1). Recurrent miscarriage (the spontaneous loss of three or more consecutive pregnancies) is a significant health issue for 1-2% of women, with no identifiable biological cause and no effective treatment. During early stages of pregnancy, complex processes help to create a uterine environment that is conducive to a successful pregnancy. These include immunological adaptation to the semiallogeneic fetus. Tolerance to paternal alloantigens is critical for successful reproduction in placental mammals (2, 3). Many studies have proposed that regulatory T cells (Tregs) play an essential role in the development of fetomaternal tolerance in mice and humans (4-7). Seminal plasma contains potent immunoregulatory molecules that contribute to the induction of tolerogenic DCs (tDCs) and ultimately Treg expansion, which is necessary to establish maternal tolerance against paternal antigens (8-10). However, the specific molecules in semen that are responsible for expansion of Tregs and establishment of maternal tolerance remain undefined.CD38, a mammalian prototype of ADP ribosyl cyclases (ADPRCs), is a type II transmembrane (TM) glycoprotein expressed in many cell types and seminal fluid (11-16). CD38 produces calcium-mobilizing second messengers, cyclic ADP ribose, and nicotinic acid adenine dinucleotide phosphate (11, 12). We previously showed that intact CD38 in prostasomes assists progesterone-induced sperm Ca 2+ signaling (13). In addition to its enzymatic role for Ca 2+ signaling, CD38 may also have a nonenzymatic role through its interaction with CD31 (17, 18). CD31, a type I TM homophilic or heterophilic receptor, is expressed in endothelial cells and a variety of immune cells (19) and is involved in attenuating the infl...

Muscle contraction and insulin induce glucose uptake in skeletal muscle through GLUT4 membrane translocation. Beneficial effects of exercise on glucose homeostasis in insulin-resistant individuals are known to be due to their distinct mechanism between contraction and insulin action on glucose uptake in skeletal muscle. However, the underlying mechanisms are not clear. Here we show that in skeletal muscle, distinct Ca 2+ second messengers regulate GLUT4 translocation by contraction and insulin treatment; D-myo-inositol 1,4,5-trisphosphate/nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose/NAADP are main players for insulin-and contraction-induced glucose uptake, respectively. Different patterns of phosphorylation of AMPK and Ca 2+ /calmodulindependent protein kinase II were shown in electrical stimuli (ES)-and insulin-induced glucose uptake pathways. ES-induced Ca 2+ signals and glucose uptake are dependent on glycolysis, which influences formation of NAD(P)-derived signaling messengers, whereas insulininduced signals are not. High-fat diet (HFD) induced a defect in only insulin-mediated, but not ES-mediated, Ca 2+ signaling for glucose uptake, which is related to a specifically lower NAADP formation. Exercise decreases blood glucose levels in HFD-induced insulin resistance mice via NAADP formation. Thus we conclude that different usage of Ca 2+ signaling in contraction/insulin-stimulated glucose uptake in skeletal muscle may account for the mechanism by which exercise ameliorates glucose homeostasis in individuals with type 2 diabetes.Both insulin and contraction induce the translocation of GLUT4 from the interior of the muscle cell to the cell membrane, leading to an increase in glucose uptake into the muscle cell (1,2). However, evidence indicates that contraction-induced GLUT4 translocation uses a mechanism distinct from that of insulin (3,4). This is the basis behind the beneficial effects of exercise in cases where insulin resistance is present, such as type 2 diabetes (5,6). However, the exact mechanisms by which insulin and contraction induce glucose transport are not clear. Ca 2+ plays a versatile role in intracellular signaling (7). Mammalian cells have specific Ca 2+ signals for particular cellular processes. Ca 2+ second messengers control intracellular Ca 2+ levels by mobilizing Ca 2+ from intracellular stores, including the sarcoplasmic reticulum, lysosomes, and mitochondria (8). D-myo-inositol 1,4,5-trisphosphate (IP 3 ), cyclic ADP-ribose (cADPR), and nicotinic acid adenine dinucleotide phosphate (NAADP) are well-characterized Ca 2+ second messengers. IP 3 is produced by phospholipase C, and the latter two by ADP-ribosyl cyclases, including CD38 (9-11). Ca 2+ signals in skeletal muscle mediate a variety of physiological processes, including muscle contraction and cell metabolism

Ca2+ signaling plays a fundamental role in cardiac hypertrophic remodeling, but the underlying mechanisms remain poorly understood. We investigated the role of Ca2+-mobilizing second messengers, NAADP and cADPR, in the cardiac hypertrophy induced by β-adrenergic stimulation by isoproterenol. Isoproterenol induced an initial Ca2+ transients followed by sustained Ca2+ rises. Inhibition of the cADPR pathway with 8-Br-cADPR abolished only the sustained Ca2+ increase, whereas inhibition of the NAADP pathway with bafilomycin-A1 abolished both rapid and sustained phases of the isoproterenol-mediated signal, indicating that the Ca2+ signal is mediated by a sequential action of NAADP and cADPR. The sequential production of NAADP and cADPR was confirmed biochemically. The isoproterenol-mediated Ca2+ increase and cADPR production, but not NAADP production, were markedly reduced in cardiomyocytes obtained from CD38 knockout mice. CD38 knockout mice were rescued from chronic isoproterenol infusion-induced myocardial hypertrophy, interstitial fibrosis, and decrease in fractional shortening and ejection fraction. Thus, our findings indicate that β-adrenergic stimulation contributes to the development of maladaptive cardiac hypertrophy via Ca2+ signaling mediated by NAADP-synthesizing enzyme and CD38 that produce NAADP and cADPR, respectively.

Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca2+ mobilizing second messenger whose formation has remained elusive. In vitro, CD38‐mediated NAADP synthesis requires an acidic pH and a nonphysiological concentration of nicotinic acid (NA). We discovered that CD38 catalyzes synthesis of NAADP by exchanging the nicotinamide moiety of nicotinamide adenine dinucleotide phosphate (NADP+) for the NA group of nicotinic acid adenine dinucleotide (NAAD) inside endolysosomes of interleukin 8 (IL8)‐treated lymphokine‐activated killer (LAK) cells. Upon IL8 stimulation, cytosolic NADP+ is transported to acidified endolysosomes via connexin 43 (Cx43) and gated by cAMP‐EPAC‐RAP1‐PP2A signaling. CD38 then performs a base‐exchange reaction with the donor NA group deriving from NAAD, produced by newly described endolysosomal activities of NA phosphoribosyltransferase (NAPRT) and NMN adenyltransferase (NMNAT) 3. Thus, the membrane organization of endolysosomal CD38, a signal‐mediated transport system for NADP+ and luminal NAD+ biosynthetic enzymes integrate signals from a chemokine and cAMP to specify the spatiotemporal mobilization of Ca2+ to drive cell migration.