The Journal of Experimental Medicine
VeriKine-HS Human Interferon-Beta Serum
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Published online 17 July 2000.
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© The Rockefeller University Press, 0022-1007/2000/7/259/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 2, July 17, 2000 259-270

Original Article

Interferon {gamma} Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy

Ali A. Ashkara, James P. Di Santob, and B. Anne Croya

a Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1
b Department d' Immunologie, Institut Pasteur, 75724 Paris, France
Dept. of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1.519-767-1450519-824-8800 ext. 4956

aashkar{at}uoguelph.ca

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-{gamma}R{alpha}–/–) 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-{gamma}R{alpha}–/– 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-{gamma}R{alpha}–/– 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.

Key Words: interferon {gamma} signaling • uterine lymphocytes • decidual spiral arteries • bone marrow transplantation • tumor necrosis factor {alpha}

Abbreviations used in this paper: BM, bone marrow; BV, blood vessels; gd, gestation day; MLAp, mesometrial lymphoid aggregate of pregnancy; PAS, periodic acid-Schiff; RAG, recombinase activating gene; Stat, signal transducer and activator of transcription; u, uterine.

© 2000 The Rockefeller University Press


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