A Chemokine, Interferon (IFN)-γ-Inducible Protein 10 kDa, Is Stimulated by IFN-τ and Recruits Immune Cells in the Ovine Endometrium1

Radical S-adenosyl methionine domain containing 2 (RSAD2) encodes a cytoplasmic antiviral protein induced by interferons (IFN). Interferon-induced with helicase C domain 1 (IFIH1) is a RNA helicase involved in innate immune defense against viruses, growth suppression, and apoptosis. Interferon tau (IFNT), a Type I IFN produced by the peri-implantation ruminant conceptus, acts on the uterine endometrium to signal pregnancy recognition and promote receptivity to implantation. Transcriptional profiling identified RSAD2 and IFIH1 as IFNT regulated genes in the ovine uterine endometrium. This study tested the hypothesis that RSAD2 and IFIH1 were induced in the endometrium in a cell type-specific manner by IFNT from the conceptus during early pregnancy. Endometrial RSAD2 and IFIH1 mRNA increased between days 12 and 16 of pregnancy, but not of the estrous cycle. In pregnant ewes, RSAD2 and IFIH1 mRNAs increased in endometrial glands, and stroma and immune cells, but not in the luminal epithelium. Neither gene was expressed in the trophectoderm of day 18 or 20 conceptuses. Progesterone (P4) treatment of ovariectomized ewes did not induce expression RSAD2 or IFIH1 mRNA in the endometrium; however, intrauterine injections of IFNT induced expression of RSAD2 and IFIH1 mRNA in endometria of ewes treated with P4, as well as in ewes treated with P4 and the progesterone receptor antagonist, ZK 136,317. These results indicate that conceptus IFNT induces both RSAD2 and IFIH1 in a P4-independent manner in the ovine uterine endometrium. These two IFNT-stimulated genes are proposed to have biological roles in the establishment of uterine receptivity to the conceptus during implantation through induction of an antiviral state and modulation of local immune cells in the endometrium.

Section: Discussionmentioning

confidence: 63%

Pregnancy and interferon tau regulate RSAD2 and IFIH1 expression in the ovine uterus

Song¹,

Bazer²,

Spencer³

2007

“…A classical ISG with reported biological effects on trophectoderm growth and adhesion in ruminants is CXCL10 (chemokine (C-X-C motif) ligand 10; alias IP-10; Nagaoka et al 2003aNagaoka et al , 2003b. CXCL10 is a member of the C-X-C chemokine family that regulates multiple aspects of inflammatory and immune responses primarily through chemotactic activity toward subsets of leukocytes.…”

Section: Cxcl10mentioning

confidence: 99%

Genes involved in conceptus–endometrial interactions in ruminants: insights from reductionism and thoughts on holistic approaches

Spencer¹,

Sandra²,

Wolf³

2008

270

253

This review summarizes new knowledge on expression of genes and provides insights into approaches for study of conceptus-endometrial interactions in ruminants with emphasis on the peri-implantation stage of pregnancy. Conceptus-endometrial interactions in ruminants are complex and involve carefully orchestrated temporal and spatial alterations in gene expression regulated by hormones from the ovary and conceptus. Progesterone is the hormone of pregnancy and acts on the uterus to stimulate blastocyst survival, growth, and development. Inadequate progesterone levels or a delayed rise in progesterone is associated with pregnancy loss. The mononuclear trophectoderm cells of the elongating blastocyst synthesize and secrete interferon-t (IFNT), the pregnancy recognition signal. Trophoblast giant binucleate cells begin to differentiate and produce hormones including chorionic somatomammotropin 1 (CSH1 or placental lactogen). A number of genes, induced or stimulated by progesterone, IFNT, and/or CSH1 in a cell-specific manner, are implicated in trophectoderm adhesion to the endometrial luminal epithelium and regulation of conceptus growth and differentiation. Transcriptional profiling experiments are beginning to unravel the complex dynamics of conceptus-endometrial interactions in cattle and sheep. Future experiments should incorporate physiological models of pregnancy loss and be complemented by metabolomic studies of uterine lumen contents to more completely define factors required for blastocyst survival, growth, and implantation. Both reduction and holistic approaches will be important to understand the multifactorial phenomenon of recurrent pregnancy loss and provide a basis for new strategies to improve pregnancy outcome and reproductive efficiency in cattle and other domestic animals.

“…In fact, Green et al (2005) reported different effects of IFNT and IFNA in the ewe, with IFNT treatment resulting in enhanced P 4 production without luteolysis while treatment with IFNA did not affect CL function and allowed normal regression of the CL. Moreover, Nagaoka et al (2003) also showed a specific effect of IFNT distinct from that of IFNA. While both IFNT and IFNA stimulated the expression of IFNg-inducible protein 10 kDa (IP-10) by monocytes, the expression of IP-10 mRNA by endometrial explants in vitro was much more effectively stimulated by IFNT (Nagaoka et al 2003).…”

Section: Discussionmentioning

confidence: 90%

“…Moreover, Nagaoka et al (2003) also showed a specific effect of IFNT distinct from that of IFNA. While both IFNT and IFNA stimulated the expression of IFNg-inducible protein 10 kDa (IP-10) by monocytes, the expression of IP-10 mRNA by endometrial explants in vitro was much more effectively stimulated by IFNT (Nagaoka et al 2003). The mRNA and protein expression levels of the lymphangiogenic factors and a marker of lymphatic vessels in the bovine CL changed significantly between the early and the mid-luteal phases of the estrous cycle (Figs 1J, K, L and 2).…”

Section: Discussionmentioning

confidence: 90%

Possible involvement of IFNT in lymphangiogenesis in the corpus luteum during the maternal recognition period in the cow

Nitta¹,

Shirasuna²,

Haneda³

et al. 2011

The corpus luteum (CL), which secretes large amounts of progesterone and is thus essential for establishing pregnancy, contains various types of immune cells that may play essential roles in CL function by generating immune responses. The lymphatic system is the second circulation system and is necessary for immune function, but the lymphatic system of the bovine CL has not been characterized in detail. We collected bovine CLs on days 12 and 16 of the estrous cycle (C12 and C16) and days 16 and 40 of early pregnancy (P16 and P40). Lymphatic endothelial hyaluronan receptor 1 (LYVE1) protein was detected in the CL by immunohistochemistry and western blotting and increased at P40 compared with C16. The mRNA expression levels of lymphangiogenic factors, such as vascular endothelial growth factor-C (VEGFC), VEGFD, and their common receptor VEGFR3, as well as the lymphatic endothelial cell (LyEC) marker podoplanin, increased in P16 and P40 CLs. Thus, it is suggested that the lymphatic system of the bovine CL reconstitutes during early pregnancy. Interferon tau (IFNT) from the conceptus in the uterus is a candidate for activating luteal lymphangiogenesis during the maternal recognition period (MRP). We found that treatment of LyECs isolated from internal iliac lymphatic vessels with IFNT stimulated LyEC proliferation and significantly increased mRNA expression of VEGFC and IFN-stimulated gene 15. Moreover, both IFNT and VEGFC induced LyECs to form capillary-like tubes in vitro.In conclusion, it is suggested that new lymphangiogenesis in the bovine CL begins during the MRP and that IFNT may mediate this novel phenomenon.