REGULATION OF MACROPHAGES 107 F4/80+ macrophages increase in the uterus during estrus and diestrus-I (Huang et al., 1995) and migrate into the uterus following implantation (reviewed by Hunt and Pollard, 1992), suggesting that estrogen or estrogen-stimulated uterine growth factors such as colony-stimulating factor- (CSF- 1) or granulocyte- macrophage colony-stimulating factor (GM-CSF) may promote their migration. In vitro assays to test estrogen as a chemoattractant have not yet been reported. However, during the early stages of preg- nancy, macrophages continue to arrive in the uterus even when CSF-1 and GM-CSF are absent (Hunt et al., 1993; reviewed by Hunt and Robertson, 1996). Possibly, chemoattraction is achieved by MIP-lc, MIP-1/3, RANTES, or JE, all of which are transcribed in pregnant mouse uterus (Robertson et al., in press). Specific message is present for all of these chemoat- tractants, but it is not yet known whether the transcripts are translated and functional proteins are produced. The numbers of macrophages are dramatically reduced in diestrus-II and proestrus uteri, and the pregnancy-stimulated influx of macrophages appears to be halted during the middle stages of pregnancy. Because progesterone is high relative to estrogen during these stages, these observations are consistent with the idea that progesterone inhibits macrophage migration. This could be (1) a direct hormonal effect on the macrophage genes that promote migration such as receptors for certain adhesion molecules, (2) associated with reduction of uterine chemoattractants, or (3) due to enhanced expression of molecules such as Fas ligand that restrict migration of activated hematopoietic cells (Griffith et al., 1995). These possibilities remain to be explored experimentally. POTENTIAL REGULATION OF UTERINE MACROPHAGE ACTIVATION BY STEROIDAL HORMONES Uterine macrophages are known to be in an activated state (high expression of Ia antigens) during the periimplantation period as well as during late stages of pregnancy (reviewed by Hunt and Robertson, 1996). Experiments are in progress to determine how activation may be achieved. Expression of Interferon-y Receptors Macrophages are primarily activated by exposure to interferon-?, (IFN-y), and there is some evidence that female steroid hormones may facilitate this activation pathway in mouse uterine macrophages. In situ hybridization studies have demonstrated associations between levels of circulating female sex steroid hormones and the intensity of signals for IFN-y receptor mRNA (o chain, IFN-yR) in uterine macro- phages. Signals are elevated in diestrus relative to other stages of the cycle, are readily detectable in the periimplantation period, and remain high in uterine macrophages throughout pregnancy (Chen et al., 1994). Presumably, increased expression of IFN-yR would enhance the sensitivity of uterine macrophages to activation by IFN-y, but this has not been demonstrated experimentally in the uterus. IFN-T in Mouse Uterus The question then arises as to whether or not IFN-y is present in cycling and/or pregnant mouse uterus. Lin et al. (1993) showed that IFN-y is detectable in early postimplantation mouse uteroplacental units by ELISA, and limited RT-PCR analyses conducted in our laboratory indicate that the IFN-y gene is transcribed at both early (day 6) and late (day 18) stages of mouse pregnancy (Platt and Hunt, 1996). The cellular source(s) of IFN-y are as yet unclear but might include uterine natural killer cells (uNK). In other contexts, NK cells initiate immune responses with IFN-y production (Sheehan and Schreiber, 1992). Alternatively, mouse placental trophoblast cells may produce IFN-y as is the case in the pig and human (LeFevre et al., 1990; Haynes et al., 1993). Interestingly and of potential relevance to pregnancy, the IFN-y gene itself is hormonally regulated; estro- gen activates the IFN- y promoter (Fox et al., 1991). Cause-and-effect relationships between IFN-y and activation of uterine macrophages via IFN-yR have