Local immune system in oviduct physiology and pathophysiology: attack or tolerance?

The local immune system in the oviduct has a unique ability to deal with pathogens, allogeneic spermatozoa, and the semi-allogeneic embryo. To achieve this, it seems likely that the oviduct possesses an efficient and strictly controlled immune system that maintains optimal conditions for fertilization and early embryo development. The presence of a proper sperm and/or embryo-oviduct interaction begs the question of whether the local immune system in the oviduct exerts beneficial or deleterious effects on sperm and early embryo; support or attack?. A series of studies has revealed that bovine oviduct epithelial cells (BOECs) are influenced by preovulatory levels of Estradiol-17ß, progesterone, and LH to maintain an immunologic homeostasis in bovine oviduct, via inhibition of proinflammatory responses that are detrimental to allogenic sperm. Under pathologic conditions, the mucosal immune system initiates the inflammatory response to the infection; the bacterial lipopolysaccharide (LPS) at low concentrations induces a proinflammatory response with increased expression of TLR-4, PTGS2, IL-1ß, NFκB1, and TNFα, resulting in tissue damage. At higher concentrations, however, LPS induces a set of anti-inflammatory genes (TLR-2, IL-4, IL-10, and PTGES) that may initiate a tissue repair. This response of BOECs is accompanied by the secretion of acute phase protein, suggesting that BOECs react to LPS with a typical acute proinflammatory response. Under physiological conditions, polymorphonuclear neutrophils (PMN) are existent in the oviductal fluid during preovulatory period in the bovine. Interestingly, the bovine oviduct downregulates sperm phagocytosis by PMN via prostaglandin E2 (PGE2) action. In addition, the angiotensin-endothelin-PGE2 system controlling oviduct contraction may fine-tune the PMN phagocytic behavior to sperm in the oviduct. Importantly, a physiological range of PGE2 supplies anti-inflammatory balance in BOEC. Our recent results show that the sperm binding to BOECs further shift the local immunity toward anti-inflammatory conditions with upregulation of IL-10, TGFß, and PGE2. In addition, this local environment leads PMN to express anti-inflammatory cytokines. In conclusion, the oviduct displays mucosal immunity that maintains an anti-inflammatory environment under physiological conditions that supports the sperm. Under pathologic condition, however, the oviduct supplies the innate immunity that may attack the sperm. Moreover, the oviduct-sperm interaction further suppresses the innate immune cells and strengthens the anti-inflammatory balance in the oviduct. Therefore, the oviduct immunity ensures sperm viability before fertilization.

Short communication: Urea induces T helper 2 (Th2) type environment at transcriptional level and prostaglandin E2 secretion in bovine oviduct epithelial cells in culture.

Excess dietary protein intake in early lactation dairy cows resulting in blood urea nitrogen of greater than 19 to 20mg/dL is associated with decreased fertility. Little is known about the local interference of urea in the normal immunological environment of the oviduct that provides optimal conditions for early reproductive events. A bovine oviduct epithelial cell (BOEC) culture was used to determine how urea influences immune environment. The BOEC monolayer was supplemented with low (20mg/dL) and high (40mg/dL) concentrations of urea together with ovarian steroids, estradiol (1ng/mL) and progesterone (1ng/mL), and LH (10ng/mL) at concentrations observed during the preovulatory period. The urea values used in this study were equivalent to 9.3 and 18.7mg/dL of blood urea nitrogen, which are typically common in lactating dairy cows with low or high protein intake, respectively. Stimulation of BOEC with 40mg/dL of urea induced gene expression of IL10 and IL4, epithelial-derived T helper type 2-driving (anti-inflammatory) cytokines as well as mPGES-1 expression and prostaglandin E2 (PGE2) secretion. However, urea concentrations of both 20 and 40mg/dL failed to alter the expression of IL1B and TNFA, Th1-driving cytokines, and the gene expression of TLR4. However, a concentration of 40mg/dL of urea stimulated α 1-acid glycoprotein expression, an acute phase protein. Data from this in vitro study suggest that urea, at least in part, contributes to influence the expression of some immune-related genes toward T helper type 2 type and prostaglandin E2 secretion, leading to disruption in local environment for fertilization and early embryonic development.

Evidence for a novel, local acute-phase response in the bovine oviduct: progesterone and lipopolysaccharide up-regulate alpha 1-acid-glycoprotein expression in epithelial cells in vitro.

Little is known about the local production and function of alpha 1-acid glycoprotein (AGP), an acute-phase protein, in the female reproductive tract. This study aimed to investigate the regulation and immune function of AGP in cultured bovine oviduct epithelial cells. Analysis by Western blotting and immunohistochemistry revealed that bovine oviduct tissue expresses AGP protein in epithelial cells and the smooth muscle layer. Stimulation of bovine oviduct epithelial cells in culture with either progesterone (1 ng/ml) or lipopolysaccharide (LPS, 10 ng/ml) induced both mRNA expression and secretion of AGP. Estradiol (1 ng/ml), progesterone (1 ng/ml), and luteinizing hormone (10 ng/ml), which are observed during the peri-ovulatory period in oviduct tissues (steroids) or in circulation (luteinizing hormone), suppressed LPS-induced expression and secretion of AGP, which in turn induced the expression of Toll-like receptor-4 (TLR-4) and interleukin-1ß (IL-1B), but suppressed TLR-2 and tumor necrosis factor-α (TNFA) expression. AGP also inhibited LPS-induced TLR-2 and TNFA expression, but had no effect on LPS-induced TLR-4 and IL-1B expression. These findings suggest that oviductal epithelial cells can participate in antimicrobial processes through the secretion of AGP, which is partly regulated by ovarian steroids. Moreover, oviductal AGP may regulate the response of epithelial cells, thereby reducing the expression of the acute pro-inflammatory cytokine TNFA, which could contribute to the local homeostasis during the acute response to endotoxin release in the oviduct's anti-infection process.