Evidence For Fibronectin Role On Uterine Natural Killer Cells Migration, Proliferation, Differentiation And Survival During Pregnancy

Fibronectin is an extracellular matrix component which has a crucial role in the establishment of a successful pregnancy. In this respectit plays an important function in cell migration. Uterine Natural Killer cells are the dominant lymphocytes found in the pregnant mammalian uterus. Studies have identified four differentiation stages of mouse uNK cells based on Dolichos biflorus agglutinin lectin cytochemistry. These differ-rentiated cells are distributed in preferential regions in the uterus throughout pregnancy. One function of these cells is the release of cytokines such as IFN-γ leading to spiral artery dilation and the maintenance of decidual integrity.Therefore these cells are essential for the normal development of decidua and placenta. When integrin expression on uNK cells was investigated in mouse uterine sections from gestation day 6 to 17it was found thata5, a6 and ß7 integrins were expressed in cells from gestation day 8 to 10 but not after gd12. Lamininwas expressed only on the antimesometrial side. ß7 integrinis an active receptor for VCAM-1 or MAdCAM-1 expressed by endothelial cells and this function promotes extra vasation of uNK cells through blood vessel walls. The absence of laminin closed to uNK cells suggests that these cells are not dependent on laminin and a6 integrin for their establishment within the extracellular matrix. However, fibronectin is present at gestation day 6 to 10 around uNK cells from the myometrium and the endometrial-myometrial junction. No staining for fibronectin was seen in the decidualized and non-decidualized endometrium near the placenta. Our results suggest that fibronectin appears to support uNK migration, proliferation, differentiation and survival in the uterus by binding toa5 integrin. The loss of a5 integrin ligation by the down regulation of fibronectin could inhibit these cellular events and perhaps unligated a5 can activelyinitiate apoptosis, possibly via a caspase 8-dependent pathway. This process has been described asintegrin-mediated cell death. © 2012 Nova Science Publishers, Inc. All rights reserved.207212Stewart, I., Peel, S., Granulated metrial gland cells in the virgin and early pregnant mouse uterus (1981) J. Anat., 133, pp. 535-54lKing, A., Loke, Y.W., On the nature and function of human uterine granular lymphocytes (1991) Immunol. Today., 12 (12), pp. 432-435. , DecCroy, B.A., Kiso, Y., Granulated metrial gland cells, a natural subset of the pregnant murine uterus (1993) Microsc. Res. 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Develop., 28, pp. 55-64Parr, E.L., Parr, M.B., Zheng, L.M., Young, J.D.E., Mouse granulated metrial gland cells originated by local activation of uterine natural killer lymphocytes (1991) Biol. Reprod., 44, pp. 834-841Van Den Heuvel, M., McBey, B.A., Hahnel, A.C., Croy, B.A., An analysis of the uterine lynphocyte-derived hobridoma cell line GWM 1-2 for expression of receptor for estrogen, progesterone and interleikin 2 (1996) J. Reprod. Immunol., 31, pp. 37-50Croy, B.A., Ashkar, A.A., Foster, R.A., Disanto, J.P., Magram, J., Carson, D., Gendler, S.J., Guimond, M.J., Histological studies of gene-ablated mice support important functional roles for natural killer cells in the uterus during pregnancy (1997) J. Reprod. Immunol., 35, pp. 111-133Hunt, J.S., Miller, L., Vassmer, D., Croy, B.A., Expression of the inducible nitric oxide synthase gene in mouse uterine leukocytes and potential relationships with uterine function during pregnancy (1997) Biol. 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Expression Of Hypoxia-inducible Factor-1α In The Cutaneous Lesions Of Balb/c Mice Infected With Leishmania Amazonensis

The hypoxia-inducible factor-1α (HIF-1α) is expressed in response to hypoxia and has been recently demonstrated in a variety of cells such as tumor cells and tumor-associated macrophages. Several characteristics of leishmanial lesions in humans and in animal models, such as microcirculation impairment, metabolic demand for leukocyte infiltration into infected tissue, parasite proliferation, and secondary bacterial infection, are strong indications of a hypoxic microenvironment in the lesions. We evaluated HIF-1α expression in the cutaneous lesions of BALB/c mice during Leishmania amazonensis infection. Immunohistochemical analyses of the lesions demonstrated, only in the later stages of infection when the lesion size is maximal and parasite burden is enormous and massive numbers of recruited macrophages and ulcers are observed, positive HIF-1α-infected cells throughout the lesions. HIF-1α is expressed mainly in the cytoplasm and around parasites inside the parasitophorous vacuoles of macrophages. This is the first evidence that macrophages in the microenvironment of lesions caused by a parasite produce a hypoxia-inducible factor. © 2004 Elsevier Inc. All rights reserved.7814954Albina, J.E., Mastrofrancesco, B., Vessella, J.A., Louis, C.A., Henry Jr., W.L., Reichner, J.S., HIF-1 expression in healing wounds: HIF-1α induction in primary inflammatory cells by TNF-α (2001) Am. J. Physiol.: Cell Physiol., 281, pp. 1971-C1977Barbieri, C.L., Giorgio, S., Merjan, A.J.C., Figueiredo, E.N., Glycosphingolipid antigens of Leishmania (Leishmania) amazonensis amastigotes identified by use of a monoclonal antibody (1993) Infect. Immun., 61, pp. 2131-2137Blouin, C.C., Pagé, E.L., Soucy, G.M., Richard, D.E., Hypoxic gene activation by lipopolysaccharide in macrophages: Implication of hypoxia-inducible factor-1α (2004) Blood, 103, pp. 1124-1130Burke, B., Tang, N., Corke, K.P., Tazzyman, D., Ameri, K., Wells, M., Lewis, C.E., Expression of HIF-1α by human macrophages: Implications for the use of macrophages in hypoxia-regulated cancer gene therapy (2002) J. Pathol., 196, pp. 204-212Chavez, J.C., La Manna, J.C., Activation of hypoxia-inducible factor-1 in the rat cerebral cortex after transient global ischemia: Potential role of insulin-like growth factor-1 (2002) J. Neurosci., 22, pp. 8922-8931Colhone, M.C., Arrais-Silva, W.W., Picolli, C., Giorgio, S., Effect of hypoxia on macrophage infection by Leishmania amazonensis (2004) J. 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Update On Pathways Regulating The Activation Of Uterine Natural Killer Cells, Their Interactions With Decidual Spiral Arteries And Homing Of Their Precursors To The Uterus

Virgin adult C57Bl/6J mouse uterus contains a population of small, non-granulated Natural Killer (NK) cells with balanced expression of NK cell activating and inhibiting LY49 receptors. Coincident with blastocyst implantation and decidualization, uterine (u)NK cells become activated. The surface glycoslyation of uNK changes, the cells proliferate and they induce production of interferon (IFN)γ, perforin, serine esterases and other molecules, including angiogenic factors. Mouse strains genetically ablated in uNK cells fail to undergo modification of spiral artery segments that branch from the uterine artery and feed into the placenta and these mice do not sustain a robust decidualization response. IFN-γ is thought, from bone marrow transplantation and therapeutic studies, to be the key uNK-cell derived mediator regulating gene expression in vascular and decidual tissues. Here, we review recent studies showing that IL-15 is the critical cytokine controlling uNK cell differentiation and that uNK cells are activated by either IL-12 or IL-18 and by other factors when both IL-12 and IL-18 are genetically absent from implantation sites. We address possible roles of the IFN-γ regulated gene α2-macroglobulin (α2-M) in regulation of the position of fetal trophoblast within the walls of the spiral arteries, and we discuss approaches that have been successful in evaluating mechanisms involved in homing of mouse uNK cell precursors to the uterus. These approaches maybe applicable to studies in women. Our studies show that complex immuno-physiological events contribute to spiral artery modification by mid-gestation in mice. © 2003 Elsevier Science Ireland Ltd. All rights reserved.592175191Anderson, S.K., Ortaldo, J.R., McVicar, D.W., The ever-expanding Ly49 gene family: Repertoire and signaling (2001) Immunol. Rev., 181, pp. 79-89Ashkar, A.A., (2000) Functions of uterine natural killer cell-derived interferon gamma in the pregnant mouse uterus, , Ph.D. thesis, University of GuelphAshkar, A.A., Croy, B.A., Interferon-gamma contributes to the normalcy of murine pregnancy (1999) Biol. Reprod., 61, pp. 493-502Ashkar, A.A., Di Santo, J.P., Croy, B.A., Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy (2000) J. Exp. Med., 192, pp. 259-270Blery, M., Olcese, L., Vivier, E., Early signaling via inhibitory and activating NK receptors (2000) Hum. Immunol., 61, pp. 51-64Boehm, U., Guethlein, L., Klamp, T., Ozbek, K., Schaub, A., Futterer, A., Pfeffer, K., Howard, J.C., Two families of GTPases dominate the complex cellular response to IFN-gamma (1998) J. 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Immunol., 3, pp. 807-813Croy, B.A., Ashkar, A.A., Foster, R.A., DiSanto, J.P., Magram, J., Carson, D., Gendler, S.J., Guimond, M.J., Histological studies of gene-ablated mice support important functional roles for natural killer cells in the uterus during pregnancy (1997) J. Reprod. Immunol., 35, pp. 111-133Croy, B.A., Black, G.P., Ashkar, A.A., Analysis of the roles of interleukin 15 during the differentiation of uterine natural killer cells (2002) Proceedings of the 19th International Natural Killer Cell Workshop, , October 2002, San Juan, PRCroy, B.A., Chantakru, S., Esadeg, S., Ashkar, A.A., Wei, Q., Decidual natural killer cells: Key regulators of placental development (a review) (2002) J. Reprod. Immunol., 57, pp. 151-168Delgado, S.R., McBey, B.-A., Yamashiro, S., Fujita, J., Kiso, Y., Croy, B.A., Accounting for the peripartum loss of granulated metrial gland cells, a natural killer cell population, from the pregnant mouse uterus (1996) J. 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Uterine Natural Killer Cells: Insights Into Their Cellular And Molecular Biology From Mouse Modelling

In primates, including women, and in rodents, natural killer lymphocytes (NK cells) have a unique relationship with the decidualizing uterus. Implantation sites from genetically modified and transplanted mice have proven useful models for understanding potential mechanisms involved in the recruitment, activation and functions of human CD56bright uterine (u)NK cells. Key findings are reviewed in this article. In mice, uNK precursor cells are recruited from secondary lymphoid tissues and are activated coincident with their uterine arrival. uNK cells proliferate, produce cytokines (interferon gamma (IFN-γ) and interleukin 18 (IL-18) and IL-27), and terminally differentiate into granulated lymphocytes. Many uNK cells proliferate within the myometrium at each implantation site forming a structure, the mesometrial lymphoid aggregate of pregnancy (MLAp) that surrounds blood vessels servicing each placenta. Post-mitotic uNK cells are abundant within decidua basalis; frequently (> 25%) associating with spiral arteries, intramurally and intraluminally. From mid-gestation, numbers of uNK cells decline. Studies of implantation sites in mice lacking uNK cells, IFN-γ, components of IFN-γ-induction and -signalling pathways or IFN-γ-regulated genes indicate that uNK cell-derived IFN-γ is essential in triggering pregnancy-induced spiral artery modification. Decidual maintenance and uNK cell death are additional effects of uNK cell-derived IFN-γ. 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Analyses of the development and glycoproteins present in the ovarian follicles of Poecilia vivipara (Cyprinodontiformes, Poeciliidae)

The morphofunctional aspects of oogenesis of Poecilia vivipara were studied aiming to understand the reproductive biology and development of species with internal fertilization, particularly those belonging to the family Poeciliidae. The stages of gonadal maturation and follicular development were characterized using mesoscopic, histological, histochemical, and lectin cytochemical analyses. Through mesoscopic evaluation the ovarian development was classified in six phases of development: immature, in maturation I, in maturation II, mature I, mature II, and post-spawn. Based on microscopic examination of the ovaries, we identified the presence of oocytes types I and II during the previtellogenic phase and types III, IV, and V during the vitellogenic phase. As oogenesis proceeded the oocyte cytosol increased in volume and presented increased cytoplasmic granule accumulation, characterizing vitellogenesis. The zona radiata (ZR) increased in thickness and complexity, and the follicular epithelium, which was initially thin and consisting of pavimentous cells, in type III oocytes exhibited cubic simple cells. The histochemical and cytochemical analyses revealed alterations in the composition of the molecular structures that form the ovarian follicle throughout the gonadal development. Our study demonstrated differences in the female reproductive system among fish species with internal and external fertilization and we suggest P. vivipara can be used as experimental model to test environmental toxicity