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Link to original content: https://pubmed.ncbi.nlm.nih.gov/10899912/
Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy - PubMed Skip to main page content
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. 2000 Jul 17;192(2):259-70.
doi: 10.1084/jem.192.2.259.

Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy

A A Ashkar  1 , J P Di Santo, B A Croy
Affiliations

Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy

A A Ashkar et al. J Exp Med. .

Abstract

The dominant lymphocytes in human and murine implantation sites are transient, pregnancy-associated uterine natural killer (uNK) cells. These cells are a major source of interferon (IFN)-gamma. Implantation sites in mice lacking uNK cells (alymphoid recombinase activating gene [RAG]-2(-/)- common cytokine receptor chain gamma [gamma(c)](-/)-) or IFN-gamma signaling (IFN-gamma(-/)- or IFN-gammaRalpha(-/)-) fail to initiate normal pregnancy-induced modification of decidual arteries and display hypocellularity or necrosis of decidua. To investigate the functions of uNK cell-derived IFN-gamma during pregnancy, RAG-2(-/)-gamma(c)(-/)- females were engrafted with bone marrow from IFN-gamma(-/)- mice, IFN-gamma signal-disrupted mice (IFN-gammaRalpha(-/)- or signal transducer and activator of transcription [Stat]-1(-/)-), or from mice able to establish normal uNK cells (severe combined immunodeficient [SCID] or C57BL/6). Mated recipients were analyzed at midgestation. All grafts established uNK cells. Grafts from IFN-gamma(-/)- mice did not reverse host vascular or decidual pathology. Grafts from all other donors promoted modification of decidual arteries and decidual cellularity. Grafts from IFN-gammaRalpha(-/)- or Stat-1(-/)- mice overproduced uNK cells, all of which were immature. Grafts from IFN-gamma(-/)-, SCID, or C57BL/6 mice produced normal, mature uNK cells. Administration of murine recombinant IFN-gamma to pregnant RAG-2(-/)-gamma(c)(-/)- mice initiated decidual vessel modification and promoted decidual cellularity in the absence of uNK cells. These in vivo findings strongly suggest that uNK cell-derived IFN-gamma modifies the expression of genes in the uterine vasculature and stroma, which initiates vessel instability and facilitates pregnancy-induced remodeling of decidual arteries.

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Figures

Figure 1
Figure 1
Photomicrographs of uNK cells in MLAp cross-sections from BM-reconstituted RAG-2−/− γc −/− mice (B–F) and nonmanipulated RAG-2−/−γc −/− mice (A) at gd 12. Excessive numbers of uNK cells (arrows) with immature appearance and poor granule development were present in MLAp of RAG-2−/−γc −/− mice receiving BM from IFN-γRα−/− or Stat-1−/− mice (E and F) compared with those receiving control B6 BM (B). e1, representative hypogranular uNK cells from E and F at higher magnification. Normal frequencies of mature uNK cells were observed in MLAp of RAG-2−/−γc −/− mice engrafted with BM from IFN-γ−/− or SCID mice (C and D). b1, representative uNK cells with normal granularity from B–D at higher magnification. No uNK cells were present in nonmanipulated RAG-2−/−γc −/− mice (A). A–F were stained with PAS. Bars, 50 μm.
Figure 2
Figure 2
Density of uNK cells in MLAp and cross-sectional area morphometry of the MLAp in engrafted RAG-2−/−γc −/− mice and control B6 mice at gd 12. The left y-axis indicates number of uNK cells per square millimeter in MLAp, and the right y-axis indicates MLAp cross-sectional area. RAG-2−/−γc −/− recipients of IFN-γRα−/− or Stat-1−/− BM cells had larger MLAp areas and higher uNK cell density than B6 BM–engrafted controls (*P < 0.01). No significant differences were found in uNK cell density and area of MLAp between RAG-2−/−γc −/− recipients of IFN-γ−/− BM or SCID BM and B6 BM–engrafted controls. Values were obtained from 11 central cross-sections per implantation site, two to three implantation sites per dam. Four to five dams were used in each experimental group.
Figure 3
Figure 3
Comparison of decidual artery remodeling at implantation sites from nonmanipulated and BM-engrafted RAG-2−/−γc −/− mice on gd 12. A is a typical cross-section of unmodified artery from an unmanipulated RAG-2−/−γc −/− mouse. C is a typical cross-section of an unmodified decidual artery in a RAG-2−/−γc −/− mouse engrafted with IFN-γ−/− BM. B–F show normal, pregnancy-induced remodeling of the spiral artery in RAG-2−/−γc −/− mice infused with BM from B6, SCID, IFN-γRα−/−, or Stat-1−/− mice, respectively. Arrows point to vessel-associated uNK cells. A–F were stained with PAS. Bars, 50 μm.
Figure 4
Figure 4
Histogram comparing mean ratios of decidual vessel/lumen diameter in unmanipulated and BM-engrafted RAG-2−/−γc −/− mice at gd 12. RAG-2−/−γc −/− mice engrafted with BM from SCID, IFN-γRα−/−, or Stat-1−/− mice or treated with mrIFN-γ (*) had lower vessel/lumen ratios compared with those of unmanipulated RAG-2−/−γc −/− mice. There were significant differences between RAG-2−/−γc −/− mice engrafted with BM from IFN-γ−/− mice, unmanipulated or treated with PBS. The mean decidual vessel/lumen diameter ratio in normal C57BL/6 mice was 1.17 ± 0.11. Values were obtained from 11 central cross-sections per implantation site, 2–3 implantation sites per dam. 4–5 dams were used in each experimental group.
Figure 5
Figure 5
Comparison of decidual morphology in unmanipulated and BM-engrafted RAG-2−/−γc −/− mice at gd 12. A shows a very hypocellular edematous decidua from an unmanipulated RAG-2−/−γc −/− mouse. C is decidua from RAG-2−/−γc −/− mice engrafted with IFN-γ−/− BM. Decidua in these recipients was either necrotic (C) or hypocellular (not shown). B–F show normal decidual morphology in RAG-2−/−γc −/− mice engrafted with B6, SCID, IFN-γRα−/−, or Stat-1−/− BM cells, respectively. Excessive numbers of uNK cells (arrows) were present in the decidua of RAG-2−/−γc −/− recipients of IFN-γRα−/− or Stat-1−/− BM (E and F) compared with control (B). A–F were stained with PAS. Bars, 50 μm.
Figure 6
Figure 6
Comparison of decidua and decidual artery morphology in pregnant RAG-2−/−γc −/− mice treated with placebo (PBS) or mrIFN-γ (1,000 U/d) for 6 d. A and C are cross-sections of unmodified spiral arteries and hypocellular decidua, respectively, from PBS-treated females. B is a cross-section of modified decidual artery from IFN-γ–treated females. D shows normal decidual morphology in IFN-γ–treated mice. A–D were stained with PAS. Bars, 50 μm.
Figure 7
Figure 7
Photomicrographs of implantation site morphology from RAG-2−/−γc −/− mice engrafted with TNF-α−/− BM (A, C, and E) or TNF-R1−/− BM (B, D, and F). uNK cells were established with normal mature morphology and cell density (A and B) compared with B6 BM–engrafted control. Decidual arteries underwent normal pregnancy-induced remodeling (C and D, compared with Fig. 3 B). Decidua had normal morphology (E and F, compared with Fig. 5 B). Arrows point to uNK cells. A–F were stained with PAS. Bars, 50 μm.
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