108 3/. yet to be established. Although both IFN-T- and IFN- yR-deficient mice are available their uteri have not been examined for the presence of Ia+ macrophages. It is entirely possible that pregnancy goes forward in these knockout mice because other types of inter- ferons (Bazer et al., 1994; Hager et al., 1994; Whaley et al., 1994) and/or tumor necrosis factor-ce (TNFc0 (reviewed by Hunt et al., 1996) substitute for IFN- HORMONAL REGULATION OF MACROPHAGE SECRETORY PROFILES A limited number of observations point to regulation of uterine macrophage secretions by female hormones and/or the cytokines they control. The data collected thus far are consistent with the idea that progesterone programs uterine macrophages into a suppressive profile. Studies Conducted In Vivo Macrophages in pregnant mouse uterus are major sites of production of the anti-inflammatory, immuno- suppressive lipid, prostaglandin E2 (PGE2) (Tawfik et al., 1986; reviewed by Hunt, 1992). Two additional anti-inflammatory cytokines, transforming growth factor-/31 and interleukin-10 (IL-10), are produced in mouse and rat uterus (Chen et al., 1993; Lin et al., 1993) but have not been established as arising from uterine macrophages. By contrast, during most of pregnancy in rats and mice, uterine macrophages contain mRNA for the cytokine, TNFce, but little TNFce protein (Hunt et al., 1993), suggesting an inhibition of production of this proinflammatory cytokine. Studies on Mouse Macrophage Cell Lines Recently, we have turned to macrophage cell lines as models for studying the impact of female sex steroid hormones on macrophage secretory profiles. Nitric oxide (NO) is a major product of activated macro- phages that might have a detrimental effect if J.S. HUNT et al. produced in high amounts during pregnancy and might, therefore, be one of the proinflammatory molecules that should be restricted. It is, therefore, of considerable interest and potential importance to pregnancy that progesterone inhibits production of this potent molecule. In macrophages, NO is produced following activa- tion of the inducible nitric oxide synthase (iNOS) gene. We tested the ability of estrogens and progester- one singly and in combination, dexamethazone (posi- tive control) and neutral lipids (negative controls), as well as estrogen and progesterone analogs to influ- ence activation of the iNOS gene promoter, steady- state levels of iNOS transcripts, and production of NO (Miller and Hunt, 1996). These experiments utilized several strategies, including transient transfection of promoter constructs into RAW264.7 mouse macro- phages and northern blots as well as substrate conversion assays in RAW264.7 cells, J774 cells, and cultured mouse bone-marrow macrophages. The results of these studies showed clearly that despite the absence of detectable PR mRNA proges- terone efficiently downregulates all three phases, that is, iNOS gene activation, accumulation of specific mRNA, and production of NO. This finding is consistent with a previous report from our laboratory, which demonstrated that progesterone downregulates iNOS in uterine mast cells (Huang et al., 1995), as well as the observation that progesterone inhibits the ability of macrophages to kill target cells (Feinberg et al., 1992). SUMMARY The data accumulated thus far are consistent with the proposition that estrogens promote an active macro- phage profile and progesterone promotes a suppressor macrophage profile. However, it is as yet uncertain whether this putative principle will hold true under changing conditions of pregnancy, when concentra- tions of certain macrophage-targeting cytokines and growth factors fluctuate. It is critical also to recognize that although experimentation in this area furthers our under-