Submitted to: American Journal of Reproductive Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/29/2004
Publication Date: 1/20/2005
Citation: Imakawa, K., Nagaoka, K., Nojima, H., Hara, Y., Christenson, R.K. 2005. Changes in immune cell distribution and IL-10 production are regulated through endometrial IP-10 expression in the goat uterus. American Journal of Reproductive Immunology. 53(1):54-64. Interpretive Summary: Biochemical communications between the developing conceptus and the mammalian uterus are important for successful implantation. A large majority of reproductive failure in cattle, sheep, and goats (ruminants) occurs as a result of an impaired signal from the developing conceptus to the maternal system. In ruminants, the gene controlling the conceptus signaling product (interferon-tau, IFNtau) is known. There are many immune cells at or near the site(s) of conceptus implantation. This could be due to recruitment or re-distribution of immune cells, but the mechanism(s) of how immune cells are redistributed near the conceptus attachment site is not known. The objective was to study the recruitment of immune cells and determine production of cytokines (soluble cell factors communicating between immune lymphoid and non lymphoid cells) and cell surface markers of white blood cells in uterine endometrium of cyclic and pregnant goats. Studies were extended to examine whether IP-10, an uterine endometrial protein regulated by IFNtau, could influence the migration of peripheral blood mononuclear cells (PBMCs) in vitro. Production of an uterine endometrial cytokine (interleukin-10) and white blood cell surface markers (CD4 and CD11b mRNA) was greater in pregnant than cyclic goat endometrium. In vitro migration of PBMCs immune cells was stimulated by goat endometrial protein IP-10. The above cellular responses may result in immune environments of the uterus more suitable for successful conceptus implantation in ruminants.
Technical Abstract: Changes in distribution or redistribution of immune cells are required for the establishment and maintenance of pregnancy, but these changes during early pregnancy have been poorly understood in the ruminant ungulates. Expression of a chemokine, interferon-gama-inducible protein 10 kDa (IP-10), identified in the endometrium of pregnant goats was stimulated by a conceptus interferon-tau (IFN-tau). It is possible that population and/or distribution of endometrial immune cells and their cytokine productions could be regulated by IFN-tau-stimulated IP-10. Using RT-PCR, expression of IP-10, IFN-gamma, TNF-alpha, IL-10, CXCR3 and leukocyte cell surface markers, CD4, CD8, CD11b and CD45 mRNA during the caprine early pregnancy was investigated. The ability of IP-10 to stimulate peripheral blood mononuclear cells (PBMCs) migration was demonstrated using a chemotaxis assay. Changes in migration of PBMCs' immune cell populations and cytokine expressions with IP-10 stimulation were investigated using flow cytometry and RT-PCR, respectively. Increases in IP-10, IL-10, CD4 and CD11b mRNA, and in CD4 and CD11b positive cells were detected in pregnant goat endometrium. Migration of PBMCs was stimulated by recombinant caprine IP-10, and the effect was significantly reduced by neutralization with the use of an anti-IP-10 antibody. In the flow cytometric and RT-PCR analyses, migrated cells stimulated by IP-10 increased the expression of IL-10 and CD11b. Furthermore, IP-10 could directly stimulate the expression of IL-10 from PBMCs. Endometrial chemokine IP-10 regulated the migration of IL-10 expressing CD11b cells, probably NK cells, and these changes may result in immune environments of the uterus suitable for conceptus implantation in ruminants.