Interferon gamma in successful pregnancies

Abstract

Interferon gamma (IFNG) is a proinflammatory cytokine secreted in the uterus during early pregnancy. It is abundantly produced by uterine natural killer cells in maternal endometrium but also by trophoblasts in some species. In normal pregnancies of mice, IFNG plays critical roles that include initiation of endometrial vasculature remodeling, angiogenesis at implantation sites, and maintenance of the decidual (maternal) component of the placenta. In livestock and in humans, deviations in these processes are thought to contribute to serious gestational complications, such as fetal loss or preeclampsia. Interferon gamma has broader roles in activation of innate and adaptive immune responses to viruses and tumors, in part through upregulating transcription of genes involved in cell cycle regulation, apoptosis, and antigen processing/presentation. Despite this, rodent and human trophoblast cells show dampened responses to IFNG that reflect the resistance of these cells to IFNG-mediated activation of major histocompatibility complex (MHC) class II transplantation antigen expression. Lack of MHC class II antigens on trophoblasts is thought to facilitate survival of the semiallogeneic conceptus in the presence of maternal lymphocytes. This review describes the dynamic roles of IFNG in successful pregnancy and briefly summarizes data on IFNG in gestational pathologies.

FIG. 1.

Schematic of IFNG signaling through the JAK/STAT1 pathway. Binding of IFNG to its receptor results in activation of the JAKs, which phosphorylate cytoplasmic monomers of STAT1. Phosphorylated STAT1 dimerizes, translocates to the nucleus, and activates transcription from gene promoters containing GAS (primary responses), such as IRF1. In the secondary responses, IRF1 activates transcription of IRF2, CDKN1A, caspases, and the MHC class Ia genes by binding IFN response elements (IRE), whereas STAT1 and IRF1 cooperate to transactivate expression of other genes, such as guanylate binding protein (GBP), PSMB8, PSMB9, and CIITA. P, phosphorylated.

FIG. 2.

Photomicrographs of hematoxylin-stained, midsagittal sections of implantation sites from mice with different genetic mutations. DBA lectin reactivity was used to distinguish uNK cells (brown-red). All images have the uterine artery and mesometrium to the top. A, B) C57BL/6J mouse at GD 6. C, D) C57BL/6J mouse at GD 10. E, F) Alymphoid (NK⁻T⁻B⁻) mouse doubly knocked out for recombinase-activating gene-2 and common cytokine chain gamma, at GD 10. G, H) Interferon receptor 1 (binds IFNA and IFNB) knockout mouse at GD 10. The left column shows low-power images. The right column shows enlarged images from the areas boxed in the left panels. M, mesometrial region; AM, antimesometrial; EC, ectoplacental cone; and V, vessel refer to structures in the preplacental interval. MLAp, mesometrial lymphoid aggregate of pregnancy; DB, decidua basalis; P, placenta; and SA, spiral artery refer to structures after placental development.

FIG. 3.

A) Between GDs 12 and 20, healthy porcine trophoblasts produce enormous amounts of IFNG. Because there is no or very weak trophoblast expression of IFNR at this time, the uterus is thought to be its target. Coincidently, uNK cells are enriched ∼3-fold, and conceptus-associated lymphocytes produce abundant IFNG transcripts. Both trophoblastic and endometrial IFNG could alter uterine epithelial cell polarity for successful conceptus attachment. Additionally, IFNG is likely to act on uNK cells (and, potentially, additional lymphocyte subtypes) to enhance their recognition of trophoblasts and their production of angiogenic factors. This would result in development of a robust, “non-hard-wired” vasculature supply for each placenta, regardless of litter size. B) In arresting early porcine attachment sites (GD 19–23), lymphocytes have stopped transcribing angiogenic genes. Lymphocytic, endometrial, and trophoblastic transcription of IFNG has been elevated to enlarge the IFNG pool at a localized conceptus attachment site. The elevation of transcripts for IFNG is greater than the accompanying elevation of transcripts for other proinflammatory cytokines (TNF and IL1B). We postulate the target of these elevated proinflammatory cytokines is the newly developed endometrial vasculature, which will be destroyed, resulting in growth arrest of the specific conceptus while adjacent littermates continue their development.