106 J.S. HUNT et al. and progesterone. Environmental programming is not novel to the uterus; in other contexts, macrophages are affected by cytokines as well as by extracellular matrix and cell-membrane components (Auger and Ross, 1992; Rutherford et al., 1993). Macrophages rapidly adapt to whatever task is at hand, and as a consequence, are phenotypically and functionally heterogenous. In this paper, we present evidence in support of the concept that uterine macrophages programmed by female steroid hormones and the powerful cytokines they unleash develop functional profiles appropriate to fertility and pregnancy. The focus is on mice, a species where compartments of the uterus are very similar to the human and the type of placentation (hemochorial) is the same. MACROPHAGE RECEPTORS FOR HORMONES AND CYTOKINES The exquisite sensitivity of macrophages to environ- mental signals is due to the presence of a wide range of receptors for modulators such as steroid hormones, polypeptide growth factors, cytokines, and bioactive lipids. Hormone Receptors Several investigators have reported the presence of estrogen receptors on macrophages and this was recently verified in our laboratory by using reverse- transcription polymerase chain reaction (RT-PCR) (Miller et al., 1996). The mouse macrophage cell lines, RAW264.7 and J774, as well as culture-derived mouse bone-marrow macrophages contained estrogen receptor (ER) mRNA. Macrophages also exhibit abundant receptors for glucocorticoids (GR) (Auger and Ross, 1992), but it is not entirely clear whether the cells express androgen receptors (reviewed by Miller and Hunt, 1996). Classical progesterone receptors (PR) cannot be identified on macrophages by direct binding nor can PR mRNA be identified by RT-PCR, yet macro- phages respond dramatically to progesterone when exposed to comparatively high concentrations of the hormone. A series of elegant studies by Werb and co- workers showed that this unexpected phenomenon is due to cross-binding of progesterone to GR (Werb, 1978; Werb et al., 1978a, 1978b). Studies done recently in our laboratory where no additive effect over dexamethazone alone was obtained when macro- phages were treated with a combination of progester- one plus dexamethazone (Miller et al., 1996) tend to support the cross-binding interpretation. Our current experiments are directed toward learning whether the same types of intracellular signaling pathways such as activation of the transcription factor inhibitor, ItBc (Baeuerle and Henkel, 1994; Scheinman et al., 1995), occur in progesterone- and glucocorticoid-treated mouse macrophages. Other Receptors Macrophages exhibit receptors for a wide range of other substances such as immunoglobulins, comple- ment components, cytokines, colony-stimulating fac- tors, peptides and neurotransmitters, iron-binding proteins such as transferrin and lactoferrin, lipopro- teins and lipids, coagulants and anticoagulants, fibro- nectin, laminin and other adhesion molecules, sugars and lectins. These have recently been listed and discussed in detail by Auger and Ross (1992). Many of these substances have been identified in the pregnant uterus where they might influence macro- phage behavior. HORMONAL INFLUENCES ON MACROPHAGE MIGRATION The mouse estrus cycle is characterized by an increase in the levels of circulating estrogen as the cycle progresses from proestrus to estrus, and an increase in the levels of circulating progesterone as the cycle continues into diestrus-I and diestrus-II (McCormack and Greenwald, 1974). Estrogens are also high during the initial and final stages of mouse pregnancy, whereas progesterone dominates during the middle stages.