Immunonutrition and immunology of reproduction in pigs

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THE REPRODUCING CAPACITY OF SOWS, A RECENT EVOLUTION The productivity of sows is dependent upon a constant control of events during each stage of the reproductive cycle. Between mating and weaning of a litter, the losses are considerable; 25 to 60% of the fertilized ova will not develop to piglets at birth and/or at weaning. The litter size of sows at parturition is a critical factor for the overall herd productivity. In fact, it would explain half of the ranking differences between the highest and the lowest third in terms of herd reproductive performance (Dagorn et al., 1998). It is generally assumed that prolificacy is determined by ovulation rate, fertilization of the ova and by the extent of embryo (or fetal) survival. In pigs, prolificacy has increased substantially during the last 10 years after several decades of stagnation. Two main genetic approaches have been used in order to develop the so-called ‘hyperprolific’ lines of pigs. The first approach is based on crossbreeding between occidental and Chinese breeds, known for their high litter size. In such case, the litter size improvement is due mainly to a high embryo survival rather than an increase in ovulation rate. However, the poor meat quality (brought by the Chinese breeds) of the progeny from these reproducing hybrid females remains to be improved (Legault, 1998). For the second approach, intensive genetic selection programs based on litter size have been used with occidental white breeds (Landrace, Yorkshire, Large White). In such cases, a considerable increase in ovulation rate (4 to 5 ova) has been achieved but, at the expense of embryo survival at the beginning of gestation. Nevertheless, the litter size is increased by 1 to 2 piglets per litter (Table 1) (Driancourt et al., 1998). PHISIOLOGICAL CONTROL OF PROLIFICACY Ovulation rate can be modified by genetic selection, feeding regimen or hormonal stimulation (Driancourt et al., 1998; Prunier and Quesnel, 1998). Nevertheless, it is not generally considered as a limiting factor for the control of litter size because the number of ova released by the ovary and fertilized is generally 15 to 40% higher than the number of fetuses carried in the uterine horns (Terqui and Martinat-Botté, 1998). In contrast to ovulation rate, fertilization rate of ova would not be a limiting factor for the control of litter size; it is generally considered to be close to 100%. Prenatal mortality, which occurs mainly during the first month of gestation, is considered as one of the main factors limiting litter size in pigs. It is also influenced by genetic selection, feeding regimen and environment. The parity is another important factor that influences embryo survival. In previous experiments carried out in our laboratories, gilts generally had a higher embryo survival rate (>80%) than multiparous sows but litter size, in this precise situation, is limited by the low ovulation rate. In fact, it has been known for years that high ovulation rate induces an increase in embryo mortality (see also Table 1). The precise mechanisms involved are not well understood but the capacity of the embryo cells for development and differentiation is impaired (Driancourt et al., 1998). THE RECOGNITION OF GESTATION: A CHALLENGE FOR THE IMMUNE SYSTEM BEFORE FERTILIZATION The process of gestation in mammals challenges the maternal immune system as early as at mating because of the presence of paternal spermatozoa and seminal proteins. In swine, as other mammals, deposition of semen into the female reproductive tract at mating induces a cascade of cellular and molecular changes that, in many aspects, resembles a classic inflammatory response (Bischof et al., 1994; Robertson et al., 1994). Within hours after mating, leukocyte infiltration occurs in the endometrium of sows (Bischof et al., 1994; Rozeboom et al., 1998). The presence of seminal plasma appears to be essential to regulate uterine immune reactions after mating and to initiate the remodeling events that prepare the endometrial tissue for implantation (Lépine et al., 2002; O’Leary et al., 2002; Robertson et al., 2002). In this way, intrauterine infusion of dead semen (Murray and Grifo, 1986; Gooneratne and Thacker, 1989; Giguère et al., 2000), and seminal or sperm antigens (Murray et al., 1983) on the estrus preceding breeding has been used in nulliparous sows but the benefit of such a practice to improve reproductive performance at first parity sows has given inconsistent responses to date. AFTER FERTILIZATION Following mating and after fecundation of ova, the optimal development of embryos is dependent upon the presence of nutritional and growth factors in uterine secretions. In pigs, uterine secretions are, at that stage, more or less like a culture media for embryos that are still free to move within the uterine lumen. In fact, the uterine secretions in pigs have been called “uterine milk” (Solymosi and Horn, 1994). This uterine medium must provide both the right amount and the balance among nutrients, hormones and growth factors for an optimal embryo development. Viable embryos contribute to the composition of this medium by producing hormones and cytokines, which influence thereafter the composition of uterine secretions; this is the so called ‘feto-maternal dialogue’ (Cox, 1997). Between 12 and 15 days of gestation, the morphology of the conceptus rapidly changes from spherical to filamentous, the implantation phase (rather an attachment in epitheliochorial placentation of pigs) starts and the embryos are fixed to uterine epithelium at precise locations until the end of gestation (Hunter, 1980). Physiological (immunological, hormonal or others) mechanisms are thought to control this phenomenon. Whatever the type of placentation or the extent of invasion of the blastocyst(s) (which are halfallogenic) in the endometrial epithelium, the process of implantation influences uterine immune response in the gestating female. The success of gestation is dependent upon a sophisticated control (and/or inhibition) of the immune system, which allows the embryos to escape the immunological rejection, attach to endometrial epithelium and develop. Moreover, this regulation must be localized within the endometrial lumen because the systemic immune system must remain efficient against external antigens. In polytocous species like pigs, another sophisticated (and fascinating) control must also occur since the conceptus (elongated blastocysts) attaches at precise locations within the uterus with a minimum overlap between each other in order to uniformly occupy the space within the uterine lumen later in gestation (Hunter, 1980). These events are regulated through complex communications at the conceptus-maternal interface. In fact, the ‘feto-maternal dialogue’ plays a key role in maternal recognition of pregnancy and in the success of gestation (Robertson et al., 1994). In this process there is now evidence based on research done in mice, humans and farm animals that leukocytes and other uterine endometrial cells under the influence of ovarian steroid hormones respond to the presence of embryos by producing a distinctive pattern of cytokines, growth factors and other metabolites such as prostaglandins (in particular PGE2) that could influence embryo attachment and development and the pregnancy outcome (Hunt and Robertson, 1996; Martal et al.,1997; Raghupathy, 1997). Receptor studies and in vitro embryo culture experiments indicate that produced cytokines target both the developing conceptus and uterine cells. These molecules are known to play important functions not only in the regulation of cell differentiation and maturation but also in the modulation of immune environment that favors embryo development and suppresses maternal rejection of conceptuses (Robertson et al.,1994; Geisert et al., 1982; Clark and Croitoru, 2001). The whole concept of immunoregulation during pregnancy and the associated cytokine production has been extensively reviewed by Robertson et al. (1994), Hunt and Robertson (1996), Mellor and Munn (2000) and Raghupathy (1997). Among the cytokines, mainly studied in humans and rodents, transforming growth factor ß2 (TGFß2), interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating-factor (GM-CSF), tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ), as well as molecules such as PGE2 have been suggested to play a role in the success of implantation and gestation (Robertson et al., 1994). Leukemia inhibitory factor (LIF) and the prolactin receptor (PRL-R) have also been shown to be important in the establishment of feto-maternal interactions (Robertson et al., 1994, Hunt and Robertson, 1996; Martal et al., 1997; Vogiagis and Salomonsen, 1999; Bartke, 1999). In pigs, Chabot (2000) showed that during the attachment period of conceptuses, the production of TGF-ß2, IL-6 and PGE2 by uterine cells was increased in a precise temporal pattern compared to uterine cells of cyclic sows. TGF-ß2 and IL-6 are multifunctional cytokines that play a major role in the regulation of cell differentiation and immune cell functions (Letterio and Roberts, 1998; Le and Vilcek, 1989). The other molecules (PGE2, GM-CSF, IFN-γ and TNF-α) have also pleiotropic effects. In the early stage of pregnancy, TGF-ß2 is produced by uterine cells and appears to be involved in tissue remodeling, regulation of the production of growth factors and the expression of cellular surface molecules, formation of extracellular matrix, and angiogenesis (Godkin and Doré, 1998; Ouellette et al., 1999; Ouellette et al., 1997; Fortin et al., 1997). In swine, it has been demonstrated that both TGFß2 and TGF-ß2 receptors are expressed by the endometrium and embryos at the time of attachment (Gupta et al., 1996; Gupta et al., 1998a; 1998b). This molecule and the two other TGF-ß isoforms are recognized to have profound effects on functional properties of immune cells, including lymphocytes, macrophages and NK cells (Letterio and Roberts, 1998). For instance, cytolytic activity of murine decidual NK cells is suppressed by TGFß2 (Saito et al., 1993). In gestating sows, the immunosuppressive activity of uterine secretions recovered on day 15 has been partially attributed to TGF-ß2 (Segerson, 1995; Segerson and Talbott, 1997). Both TGF-ß2 and PGE2 are also known to inhibit production of interleukin-2 (IL-2) from human T cells (Demeure et al., 1997; Letterio and Roberts, 1998). Interleukin-2 is known to increase cytotoxic activity of NK cells against human and porcine trophoblastic cells (King and Lowe, 1990; Yu et al.,1994). In pregnant sows, the conceptus and the endometrium secrete large amounts of PGE2 (Lewis and Waterman, 1983; Bazer et al., 1984). Prostaglandin E2 is critical in early gestation for vascular permeability, placental development and immune response of pigs (Kennedy, 1977; Geisert et al., 1990). During the post-attachment period, allantoic fluid variations of PGE2 concentration on day 30 of gestation have been positively associated with litter weight variations in sows (Giguère et al.,2000) (Figure 1). It is known that the concentration of intrauterine PGE2 is higher in Chinese hyperprolific Meishan than in occidental Yorkshire-Landrace sows at the beginning of gestation (Bazer et al., 1984). Because of the important role of PGE2 in embryonic survival and in the success of gestation (Giguère et al., 2000), differences in regulation of PGE2 secretion may be a possible explanation for the genotype differences in prolificacy. The precise mechanism by which PGE2 is involved in porcine embryonic growth and development is not known. This molecule is suspected to play a key role in the establishment of gestation in different species by reducing (as for TGF-ß2) the cytotoxic activity of natural killer (NK) and lymphokine-activated killer cells in mice (Mathews and Searle, 1987), these cells being capable of recognizing and directly lysing porcine trophoblastic cells (Gupta et al., 1998a). Prostaglandin E2 also regulates the secretion of factors such as GM-CSF that are beneficial for the development and survival of murine and bovine embryos (De Moraes and Hansen, 1997; Robertson et al., 1999; Émond et al., 1998; Émond et al.,2000). Leukemia inhibitory factor (LIF) and IL-6 belong to the same cytokine family and can act in both pro-inflammatory and anti-inflammatory ways (Gadient and Patterson, 1999). During the implantation period, LIF plays an important role in several species. This receptor is expressed by preimplantation embryos (mouse, human, cow and sheep) (Stewart, 1994). The presence of LIF is essential in mice to support implantation (Stewart et al., 1992). Mice lacking a functional LIF gene are unable to support implantation. Embryos need this signal for normal implantation. Similarly, knockout mice for the receptor of PRL were unable to support implantation (Bartke, 1999). Although IL- 6 shares many biological properties of LIF (Gadient and Patterson, 1999), its role is not as clear during the implantation period. As for other cytokines, IL- 6 has pleiotropic effects and can be produced by different types of cells (Van Snick, 1990). Its expression in the uterus seems to be activated by the presence of the embryos in mice (De et al., 1993) and pigs (Chabot et al., 2000). In swine, its expression in both the endometrium and placenta is also evident at days 18, 30 and 60 of pregnancy (Modric et al., 2000). It has been recently demonstrated that IL-6 mRNA expression in uterine tissue of pregnant sows peaked at 15 days of gestation while in cycling sows the expression remained low (Chabot et al., 2000). The function of IFN-γ at the feto-maternal interface is still unknown, but results suggest that it plays a role in the maintenance of early pregnancy by modulating the production of different factors by endometrial cells (Nasu et al., 1998). Despite their similar origin, porcine trophoblastic IFN-γ does not have an antiluteolytic activity like ruminant trophoblastic IFN (Martal et al., 1997; Lefèvre et al., 1998). Recently, it was reported that porcine IFN-γ receptor is expressed not only on uterine epithelium but also on the trophoblast and peaks on day 16 of gestation (D’Andrea and La Bonnardière, 1998). It has been recently observed that the peak in TGF-ß2 and IL-6 coincides with the peak of IFN-γ in the uterine secretion (Chabot et al., 2000). These results suggest that secreted trophoblastic IFN-γ may play a role in regulation of these genes. IFN-γ is a multifunctional cytokine that regulates, in a wide variety of cells and tissues, more than 200 genes involved in cellular maturation, differentiation, activation and apoptosis (Boehm et al., 1997). Recent results showed that IFN-γ regulates the production of IL-6, IL-8 and other cytokines by human endometrial stromal cells (Nasu et al., 1998). Therefore in reproduction, trophoblastic IFN-γ may play a key role in regulation of genes involved in tissue remodeling and embryo attachment. TNF-α has been found in maternal, placental and fetal tissues (Argilés et al., 1997); and its presence in high concentrations is deleterious for the survival of embryos (Pampfer et al., 1994). In fact, it has been recently identified in situations of nutrient deficiency such as vitamin A or iron (Ashworth and Antipastis, 2001; Antipastis et al., 2002). Therefore, its beneficial role in the early stage of pregnancy is questionable. Figure 2 illustrates and summarizes some of the mechanisms involved in the above-described ‘fetomaternal dialogue’. In this proposed model, embryos first signal their presence by secreting estradiol (E2) around day 12 of gestation. In response to this signal, the uterine tissue, under the effect of progesterone (P4), secretes factors essential to successful attachment. Among these factors, LIF and TGFß2 have been shown to play a key role in other species. In response to uterine signals, embryos secrete IFN-γ and possibly other factors and express receptors for molecules involved in the attachment process. These signals sent by the embryos through IFN-γ and E2 to the uterine tissue are probably important for the successful attachment of embryos. In response to embryonic signals, different factors, which include PG, TGFß2, IL-6, angiogenic factors and many others, are produced by uterine tissue. The uterine media must provide nutrients both in right amount and balance with hormones and growth factors for an optimal embryo development. THE CONCEPT OF IMMUNONUTRITION During recent years (mostly since the early 1980s), an increasing number of substrates have been recognized for their immuno-modulating function. Macro- and micronutrients have been identified as so-called immunonutrients (Suchner et al., 2000). This is the case for some amino acids (arginine, cysteine, tryptophan (Melchior et al., 2002) and taurine), nucleotides and lipids (specifically, polyunsaturated fatty acids (PUFA)) (Suchner et al., 2000). Some micronutrients such as vitamins (A, C and E) as well as trace elements (Cr, Zn and Se) have also been reported to interact with the immune system (Lessard et al., 1991; Suchner et al., 2000; Spears, 2000). It appears that the dietary levels of these nutrients required for ‘immunoefficiency’ exceed the amount needed to prevent appearance of classical deficiency symptoms. Traditionally, the nutrient requirements for immune functions have been considered part of the overall maintenance requirements. However, the immunomodulation properties of high levels of some nutrients challenge this generally accepted idea. In fact, the concept of immunonutrition implies that the dietary level of a given nutrient must cover both the metabolic and immunological needs of the animal (Suchner et al., 2000). The concept of immunonutrition has been developed in humans and animals mainly in relation to its impact on reinforcement of the immune systemand its ability to resist disease (Suchner et al., 2000; Spears, 2000). However, in the case of immunology of reproduction, different (even opposite) mechanisms of immune system modulation are likely to be involved since the main objective is a local inhibition or the attenuation of the immune system toward the protection of embryos. Most of the studies investigating the role of feeding and/or specific nutrients in either reproduction or immunology of reproduction have used nutrient deficiency models to identify the mechanisms involved. Although informative, such an approach might not apply to a concept of immunonutrition for reproduction where the dietary level of a given nutrient will have to cover, as mentioned earlier, both the metabolic and immunomodulation needs for optimal reproduction. The information available on the effect of nutrients on immunology of reproduction and embryo survival is rather scattered. Nevertheless, it allows us to understand and/or speculate on different immune concepts and metabolic pathways that promote successful outcomes of pregnancy. Possibly, the macro- and micronutrients involved in the immunomodulation of reproduction are likely to be the same as those identified for the regulation of the whole immune system. IMMUNONUTRITION AND IMMUNOLOGY OF REPRODUCTION MACRONUTRIENTS Amino acids, the case of tryptophan and arginine As far as protein metabolism is concerned, recent works have demonstrated that the catabolism of tryptophan is involved in the fetal defense against the maternal immune system and could represent a novel means of immunoregulation in polytocous species (Munn et al., 1998; Mellor and Munn. 1999; Mellor and Munn. 2000). Indeed, in early gestation IFN-γ induces in macrophages (local immune cells) a strong expression of the enzyme indoleamine dioxigenase (IDO) (see Figure 3), which initiates a pathway for the catabolism of tryptophan (as cited by Munn et al., 1998). At the same time, trophoblastic embryo cells are capable of a preferential transport of the locally (endometrial) available tryptophan. These two phenomena would create a tryptophan depletion at the cellular microenvironment of the feto-maternal interface. This would suppress other local immune cells (in particular, T cells), which need tryptophan to proliferate and then suppress embryo rejection. Such a function and tissue distribution of IDO might be linked to the fact that tryptophan is the less abundant amino acid and could therefore be a target for cellular regulatory mechanisms. In a polytocous species like mice, this metabolic utilization of tryptophan at the feto-maternal interface is important enough to induce a decrease in systemic tryptophan (Munn et al., 1998; Mellor and Munn. 1999). It appears, therefore, that the metabolic vigor of the embryo would ensure its own protection against the cytotoxic activity of the endometrial immune system. Therefore, the most fragile embryos are not likely to survive in such a situation with the consequences appearing in litter size later in gestation and at parturition. As far as arginine is concerned, the information is rather limited. The conceptus and the uterine tissue, by catabolizing arginine through the activation of nitric oxide synthetase enzymes, produces nitric oxide (NO) (Purcell et al., 1999). In this context, NO has been shown to be important in early embryonic survival (Gouge et al., 1998) and may contribute to the success of implantation by stimulating angiogenesis, maintaining vasodilatation and preventing the coagulation of platelets on the trophoblast surface during the process (Gagioti et al., 2000). Fatty acids The importance of prostaglandins (PG) in the control of reproduction and on immunology of reproduction has been mentioned earlier. The importance of nutrition for their homeostasis is critical since their metabolic precursors are fatty acids (Figure 4). Arachidonic acid (C20:4n-6) is the immediate precursor of the 2-series PG. It is bioavailable either directly from the diet or via desaturation and elongation reactions (Levine, 1988) and is one of the most abundant fatty acids in the phospholipids of mammalian cellular membranes (Shapiro et al., 1993). The synthesis of 2-series PG is controlled by the presence and activity of the cyclooxygenase (COX) enzymes (Dubois et al., 1993). Two different genes encode for COX: COX1 and COX2. Cyclooxygenase 1 is considered as a constitutive enzyme while COX2 synthesis is locally activated in response to growth factors or cytokines (Smith and Dewitt, 1996). Recent observations suggested that COX1 would be critical for the modulation of porcine endometrial secretion of PGE2 (Guay et al., 2003a). Such a hypothesis contrasts with results reported for bovine and ovine endometrium, where PGE2 secretion and production are controlled primarily through the COX2 expression (Charpigny et al., 1999; Fortier et al., 2000). Eicosapentanoic acid (C20:5n-3), a precursor of the 3-series PG, and conjugated linoleic acids (CLA) (Li and Watkins, 1998) is known to compete at the COX level with C20:4n-6. The balance among these fatty acids and the affinity for the enzymes determine the quantity and the type of PG synthesized. Linolenic acid (C18:3n-3) is precursor of C20:5n- 3, whereas C20:4n-6 is derived from linoleic acid (C18:2n-6). In this last case, an intermediate metabolite, dihomo-γ-linolenic acid (C20:3n-6), is precursor of both C20:4n-6 and the 1-series PG. It has been recently shown (Chartrand et al.,2003) that dietary enrichment in C18:2n-6 and C18:3n-3 can influence the fatty acid composition of plasma and endometrial tissues and modulate systemic PGE2 concentration during early pregnancy in gilts. However, C18:2n-6 enriched diets were not efficient in increasing total PGE2 and PGF2α recovered in the uterine fluid whereas C18:3n-3 decreased both PG drastically. This difference appears to be due to the fact that C18:2n- 6 is not efficient in modulating local C20:4n-6 concentrations, whereas C18:3n-3 decreased C20:4n-6 by 30% and increased by more than 5-fold the C20:5n-3 content of endometrial tissues. It appeared, in that experiment, that the C18:3n-3enriched diet had a detrimental effect on the uterine environment and the well being of the embryos in early pregnancy. Although further studies are required to confirm and eventually explain these results, it has been demonstrated previously (Amusquivar et al., 2000) that an excess of n-3fatty acids in the maternal diet could induce a specific deficiency of C20:4n-6 in the fetuses. In such cases, the effect is either due to the direct inhibitory action of n-3 fatty acids on ∆6 desaturation within the fetus and/or indirectly to an altered proportion of fatty acids for placental transfer. The metabolism of arachidonic acid appears very early in embryo development (Sayre and Lewis, 1993). They hypothesized that PGE2 and PGF2α may be involved in the transition from spherical to elongated embryos, since on day 4 of development, ovine embryos can convert C20:4-6 to several compounds, including PG. MICRONUTRIENTS The case of folic acid (vitamin B9) In pigs, supplements of B9 to sows have been reported to increase litter size and embryo survival (Matte et al., 1984; Lindemann and Kornegay, 1989; Thaler et al., 1989; Tremblay et al., 1989). However, the effect is not always constant since absent or attenuated responses to B9 supplements have been reported for litter size and embryo survival (Harper et al., 1994; 1996) mainly in nulliparous sows (Lindemann and Kornegay, 1989; Matte et al., 1993; Giguère et al., 2000; Guay et al., 2002a). The B9 supplement induces a decrease in uterine estradiol-17B (E2) content in sows in early pregnancy (day 15) (Duquette et al., 1997; Guay et al., 2003a). Matte et al. (1996) have also noted a lower in vitro secretion of E2 by conceptus homogenates in response to B9 supplement in multiparous sows. During conceptus elongation, porcine conceptus secretion of estrogens increases rapidly (Geisert et al., 1982). This progressive increase is followed by a rapid decline, and then uterine content of E2 rises again after day 15 (Geisert et al., 1990), suggesting a developmental regulation of E2 secretion by conceptuses. Thus, the decreases in uterine content of E2 in B9-supplemented sows suggest modifications in the regulation of conceptus development (Guay et al., 2003a). This alteration in uterine E2 content by B9 supplementation was not associated with a modification of conceptus expression levels of cytochrome P450 mRNA; modifications of conceptus enzymatic activities, related to other aspects of E2 metabolism, could be involved (Guay et al., 2003a). Dietary supplements of B9 also increase the uterine content of PGE2 during the conceptus attachment (day 12 to 15 of gestation) in sows (Matte et al., 1996; Duquette et al., 1997) or later in gestation in allantoic fluid (day 25) (Giguère et al., 2000; Guay et al., 2003b), (see Table 2). Nevertheless, as for the effect of B9 on litter size and embryo survival, the response of endometrial PGE2 to dietary supplementation of B9 is not constant (Guay et al., 2003a). It might be due to the stage of gestation chosen or to differences in the supply of arachidonic acid (C20:4n-6 ) in the endometrial tissue. As stated previously, biosynthesis of PG is dependent upon the presence of its precursor, arachidonic acid, and the activity of cyclooxygenases, COX1 and COX2, rate-limiting enzymes for PG. Another factor is the fact that there are other sources of PGE2 within the endometrium lumen. Indeed, several authors have observed ability of the pig conceptus for prostaglandin synthesis (Davis et al., 1983, Lewis, 1989). Davis et al. (1983) observed low phospholipase A2 activity on days 7-11 of pregnancy followed by an increase during conceptus elongation providing arachidonic acid for prostaglandin production. Recently, Wilson et al. (2002) showed that COX2 mRNA is highly expressed in filamentous pig conceptus but not in spherical conceptus. Links between folate and prostanoid (prostaglandin family) metabolism have been established before. In rats, folate deficiency induced a marked increase in thromboxane A2 and B2 secretion by blood platelet (Durand et al., 1996). This specific effect of folate deficiency would be mediated by a substantial increase in homocysteine (Durand et al., 1997), a detrimental intermediate metabolite of the B12-dependent remethylation pathway of methionine (Figure 5), which is known to stimulate biosynthesis of thromboxane B2 and arachidonic acid release by blood platelets (Signorello et al., 2002). However, it has also been demonstrated that homocysteine decreased secretion of prostacyclin by arterial endothelial cells markedly (Demuth et al., 1999). A recent study has shown that a dietary folic acid supplement of 15 ppm during the first 15 days of gestation reduced plasma and uterine flushing concentrations of homocysteine in gestating sows (Guay et al., 2002b). However, no information is available on specific effects of homocysteine on prostaglandin metabolism of endometrial tissue. The B9 supplement decreased endometrial expression of IL-2 in sows at the time of attachment (day 15) in pigs (Guay et al., 2003a). Interleukin-2 increases the cytotoxic activity of endometrial NKlike cells in vitro (Yu et al., 1994), these cells being capable of recognizing and directly lysing porcine trophoblastic cells. Elevated NK cell activity was recorded in pregnant pigs on days 10 and 20 of gestation but not in cyclic sows (Yu et al., 1993). In fact, administration of IL-2 (beginning 1 day after implantation) induces abortion and embryonic resorption in gestating mice (Lala et al., 1990). The link between the expression of IL-2 and folic acid may be related to other immunological regulatory factors, in particular the nuclear factor- κB (NF- κB) (Jain et al., 1995). This ubiquitous transcription factor, which is a key regulator of pro-inflammatory cytokine release (Lappas et al., 2002), is stimulated by interleukin-1ß, TNF-α, platelet-activating factor and oxidants (H2O2 and ozone) (Barnes and Karin, 1997) and induces production of IL-2 and several other cytokines (Gosh et al., 1998). In vitro, homocysteine, a pro-oxidative metabolite that is accumulated in plasma during a B9 deficiency (Huang et al., 2001), can stimulate NF-κB activity in vascular smooth-muscle cells (Wang et al., 2000). As mentioned previously, a dietary folic acid supplement of 15 ppm during the first 15 days of gestation reduced plasma and uterine flushing concentrations of homocysteine in gestating sows (Guay et al., 2002b). Therefore, a reduction of endometrial expression level of IL-2 might be mediated by an effect of B9 on uterine homocysteine. However, further studies are necessary to evaluate direct effects of homocysteine on endometrial expression of IL-2 mRNA. Dietary supplementation with folic acid appeared also involved in the modulation of endometrial GMCSF by decreasing its expression at day 25 of gestation (Guay et al., 2003b). This is possibly related to endometrial metabolism of prostaglandin and of TGF-ß2, both being influenced by dietary supplements of folic acid (Table 2). The precise mechanism involved in the interaction among PGE2, TGF-ß2 and GM-CSF at the endometrial level of sows is not clear; both PGE2 and TGF-ß2 have in vitro stimulating or inhibiting effect on GM-CSF, depending upon the type of lymphocytes in culture. Indeed, it has been shown that, while a pretreatment with TGF-ß2 increases the production of GM-CSF by human lymphocytes (Demeure et al., 1997), TGF-ß2 could inhibit the positive action of interleukin-2 on production of GM-CSF by decidual large granular lymphocytes (Jokhi et al.,1994). Similarly, it was reported that PGE2 may stimulate the production of GM-CSF by human lymphocytes (Demeure et al., 1997; Fortin et al., 1997); but is also known to inhibit, through the activation of the cAMP-dependent signaling pathway, the GM-CSF production by human peripheral lymphocytes (Borger et al., 1996; Sottile et al., 1996). In fact, as stated previously, endometrial variations of TGF-ß22 and PGE2 may affect directly the embryonic attachment as well as placental and endometrial vascularization during the first 25 days of gestation (Kraeling et al., 1985; Laiho and Keski-Oja, 1989; Hamilton and Kennedy, 1994; Doré et al., 1996). CONCLUSION Although the modulating effect of nutrients on the immune system is well accepted in classical immunology (Suchner et al., 2000), the concept of immunonutrition is a new and fascinating area of research that is just emerging in reproduction. Taken together, all this information in reproducing sows shows that the mechanisms for control of reproductive performance are related to a delicate and complex balance among immune, hormonal and nutritional factors that are critical for the success of reproduction. 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