The long term goal of this project is to define mechanisms involved in regulating the uterine mucosal immune system. Pregnancy or use of oral contraceptives can alter the mucosal immune system and increase susceptibility to infectious diseases. Additionally, the fetus alters uterine immune function resulting in protection of the fetal agents from crossing the utero-placenta and infecting the fetus. The role that steroid hormones play in implications to treatment of sexually transmitted diseases, to blocking transmission of viruses such as the human immunodeficiency virus from mother to fetus, and to our understanding of how pharmacological manipulation of cycling females may be impacted by cyclic changes in endogenous steroid hormones. Our preliminary results demonstrate that one component of the uterine anti-viral mechanisms, expression of the anti-viral protein Mx, is dramatically affected by steroid hormones and interferon. To test this hypothesis we propose to utilize cell cell lines derived from the bovine uterine lumenal (LE) and glandular (GE) epithelium and stroma (ST) and peripheral blood mononuclear cells (PBMC) filtered through the uterus to address the following specific aims: 1.) Determine the effects of steroids and IFN on Mx expression and anti-viral activity of LE, GE, ST and PBMC; 2.) Determine the effects of paracrine interaction between PBMC and LE, GE and ST cells on Mx expression and antiviral activity; and 3.) Determine the effect of level of Mx expression in the presence and absence of IFN and steroid hormones on antiviral activity of LE, GE and ST. Cell culture and co-culture in the presence and absence of interferon and steroid hormones will be utilized to assess affects on steady-state levels of Mx mRNA and protein and antiviral activity of the uterine cell lines against challenge with Vesicular Stomatitis virus. Paracrine (physical and biochemical) interactions between the uterine cell lines and PBMC will be evaluated to address the potentially complex cellular interactions that occur in the uterus in response to viral infection. Results will provide novel information on the role played by steroid hormones in regulating the antiviral response.
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