Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Oct 14;22(20):11094.
doi: 10.3390/ijms222011094.

Interleukin-15 in Outcomes of Pregnancy

Scott M Gordon  1   2
Affiliations
Review

Interleukin-15 in Outcomes of Pregnancy

Scott M Gordon. Int J Mol Sci. .

Abstract

Interleukin-15 (IL-15) is a pleiotropic cytokine that classically acts to support the development, maintenance, and function of killer lymphocytes. IL-15 is abundant in the uterus prior to and during pregnancy, but it is subject to tight spatial and temporal regulation. Both mouse models and human studies suggest that homeostasis of IL-15 is essential for healthy pregnancy. Dysregulation of IL-15 is associated with adverse outcomes of pregnancy. Herein, we review producers of IL-15 and responders to IL-15, including non-traditional responders in the maternal uterus and fetal placenta. We also review regulation of IL-15 at the maternal-fetal interface and propose mechanisms of action of IL-15 to facilitate additional study of this critical cytokine in the context of pregnancy.

Keywords: CD122; Interleukin-15; inflammation; macrophages; natural killer cells; placenta; pregnancy; trophoblast.

PubMed Disclaimer

Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Components of IL-15 receptors and signaling cascades in IL-15-responsive cell types at the maternal–fetal interface. NK cells express CD122 and the common gamma chain (γc) and activate JAK-STAT, Akt, and MAP kinases in response to IL-15 presented in the context of IL-15Rα. IL-15 drives numerous functions in killer lymphocytes, including classical and uterine NK cells. Emerging IL-15-responsive cell types, such as CD122+ macrophages (CD122+ Mac) and CD122+ extravillous trophoblasts (EVT), may express alternative forms of the IL-15 receptor and activate non-classical signaling cascades downstream of IL-15. Created with Biorender.com, accessed 3 October 2021.
Figure 2
Figure 2
Spatial and temporal regulation of IL-15 during the menstrual cycle and during gestation has multiple effects during pregnancy. IL-15 is produced and presented by decidual stromal cells (DSCs) and macrophages (Macs) in the uterus. IL15 is induced during the late secretory phase, when progesterone is dominant. Transcription of IL15 is induced by the progesterone receptor (PGR) and GATA2. HAND2 binds the IL15 promoter directly and induces IL15 in DSCs but represses it in endometrial stromal fibroblasts, precursors to DSCs. Drawing on murine data, IL-15Rα peaks post-implantation, at the time of uterine spiral artery remodeling. The presumed abundance of IL-15/IL-15Rα complexes during that time expands murine DBA+ uterine NK cells and drives differentiation of KIR+CD39+ NK cells in human decidua. In the placenta, trophoblasts can produce IL-15 early in gestation at low levels but produce IL-15 maximally late in gestation during spontaneous labor. Created with Biorender.com, accessed 3 October 2021.
See this image and copyright information in PMC

References

    1. Carson W.E., Giri J.G., Lindemann M.J., Linett M.L., Ahdieh M., Paxton R., Anderson D., Eisenmann J., Grabstein K., Caligiuri M.A. Interleukin (IL) 15 Is a Novel Cytokine That Activates Human Natural Killer Cells via Components of the IL-2 Receptor. J. Exp. Med. 1994;180:1395–1403. doi: 10.1084/jem.180.4.1395. - DOI - PMC - PubMed
    1. Puzanov I.J., Bennett M., Kumar V. IL-15 Can Substitute for the Marrow Microenvironment in the Differentiation of Natural Killer Cells. J. Immunol. 1996;157:4282–4285. - PubMed
    1. Kennedy M.K., Glaccum M., Brown S.N., Butz E.A., Viney J.L., Embers M., Matsuki N., Charrier K., Sedger L., Willis C.R., et al. Reversible Defects in Natural Killer and Memory CD8 T Cell Lineages in Interleukin 15-Deficient Mice. J. Exp. Med. 2000;191:771–780. doi: 10.1084/jem.191.5.771. - DOI - PMC - PubMed
    1. Becker T.C., Wherry E.J., Boone D., Murali-Krishna K., Antia R., Ma A., Ahmed R. Interleukin 15 Is Required for Proliferative Renewal of Virus-Specific Memory CD8 T Cells. J. Exp. Med. 2002;195:1541–1548. doi: 10.1084/jem.20020369. - DOI - PMC - PubMed
    1. Koka R., Burkett P.R., Chien M., Chai S., Chan F., Lodolce J.P., Boone D.L., Ma A. Interleukin (IL)-15Rα–Deficient Natural Killer Cells Survive in Normal but Not IL-15Rα–Deficient Mice. J. Exp. Med. 2003;197:977–984. doi: 10.1084/jem.20021836. - DOI - PMC - PubMed

LinkOut - more resources