Journal of Reproductive Immunology, 22 (1992) 257-268

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Elsevier Scientific Publishers Ireland Ltd.

JRI 00784

Differential distribution of interleukin-lc and interleukin-lfl proteins in human placentas X i a o - L i n g H u , Y a p i n g Y a n g a n d J o a n S. H u n t Department of Pathology and Oncology, University of Kansas Medical Center, Kansas Oty, KS (USA) (Accepted for publication 24 April 1992)

Summary Interleukin-lct (IL-lot) and interleukin-lfl (IL-lfl) were identified in samples of first trimester and term placentas by immunocytochemistry using two sets of polyclonal antibodies to recombinant IL-1. All samples contained the two species of IL-1, which predominated in different types of cells: IL-lct was contained primarily in placental villous trophoblastic and stromal cells whereas IL-IB was localized to cells in fetal and maternal blood. With respect to the cellular localization of the two proteins, early and late gestation tissues were similar. Although these results were generally consistent for the two sets of antibodies, differences were noted in the binding patterns of the individual reagents. The findings in this study provide strong support for the postulate that IL-I modulates placental development and suggest that IL-lo~ may be the preferred species in extraembryonic tissues. Key words:

immunocytochemistry; interleukin-1; macrophage; placenta;

trophoblast Introduction Interleukin-1 (IL-1), a Mr 17 000 polypeptide growth factor that is widely conserved among species and is produced in many types of cells, consists of Correspondence to: Joan S. Hunt, Ph.D., Dept. of Pathology and Oncoiogy, University of Kansas Medical Center, 39th St. and Rainbow Blvd., Kansas City, KS 66103, USA. 0165-0378/92/$05.00 © 1992 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

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two species, IL-lot and IL-1/~ (March et al., 1985; Oppenheim et al., 1986). IL-lo~ and IL-1/3 bind to the same receptor (Sims et al., 1988), which is expressed on a wide variety of cell types (Dower and Rudal, 1987) and exert similar effects on cellular functions (Oppenheim et al., 1986; Beresini et al., 1988). The two proteins stimulate the production of hematopoietic and other growth factors, regulate the synthesis and secretion of various inflammationassociated molecules such as acute phase proteins, collagenase and prostaglandins and have concentration-dependent, pleiotrophic effects on cellular proliferation (Elias et al., 1987; Lindholm et al., 1987; Mochizuki et al., 1987; Le and Vilcek, 1987; Dinarello, 1988). In general, production of IL-1 is associated with inflammatory stimuli such as endotoxin (reviewed by Le and Vilcek, 1987; Dinarello, 1988). It is therefore somewhat surprising that normal human placentas appear to be sites of synthesis of this cytokine. Cytotrophoblastic cells isolated from term placentas contain IL-1 mRNA (Main et al., 1987) and IL-1/3 mRNA has been identified in homogenates of decidua and placental membranes by Northern blot hybridization (Kauma et al., 1990). Bioassays have identified IL-1 production by placental macrophages (Flynn et al., 1982) and IL-lo~ and IL1~ have been reported in normal amniotic fluid (Tamatani et al., 1988; Romero et al., 1989; Tsunoda et al., 1990). Human placentas taken from early and late stages of gestation have not been examined by immunohistology for IL-1 proteins. Systematic localization studies could be helpful in identifying the cellular sources of IL-1 c~ and IL-l~3 inasmuch as cells transcribing the growth factor genes often contain high levels of the proteins (Tamada et al., 1990; Chen et al., 1991; Yelavarthi et al., 1991) and might also provide some clues as to cellular utilization. The purpose of this study was therefore to determine which cells in placental tissues contained IL-la and IL-1/3 proteins and to compare the findings in first trimester and term placentas. Materials and Methods Tissues

Three specimens each of first trimester placenta, term placenta and term extraplacental membranes were obtained under a protocol approved by our institutional Human Subjects Committee in cooperation with C.R. King, Department of Obstetrics and Gynecology. First trimester tissues, estimated at 8-12 weeks of gestation by date of previous menstrual period, were acquired from elective pregnancy terminations and term tissues were obtained from cesarean deliveries that were performed to avoid potential fetal distress. Two or three samples (approximately 0.5-1 cm 3 portions) were dissected from first trimester placentas, cotelydons in term placentas and reflected am-

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niochorion membranes. The samples were fixed overnight at 4°C in freshly prepared 4% paraformaldehyde dissolved in phosphate buffered saline (PBS, pH 7.2-7.4) and were embedded in paraffin. Sections (5/zm) from the paraffin blocks were taken onto glass slides for testing by immunocytochemistry.

Reagents Monospecific rabbit antibodies to recombinant IL-lot and IL-1/3 were generous gifts from S. Gillis, Immunex Corporation, Seattle, WA. A second set of rabbit antibodies to IL-1 was purchased from Cistron Biotechnology, Pine Brook, NJ. Recombinant molecules were used as immunogens for both sets of antibodies, both were supplied as unpurified sera and tests were conducted by the suppliers to verify specificity. Throughout this report, the IL-1 reagents are identified by source as anti-IL-la(I) and anti-IL-lfl(I) (Immunex reagents) and anti-IL-lot(C) and anti-IL-lfl(C) (Cistron reagents). Following titration experiments to determine optimum concentrations for immunostaining of placentas, the Immunex reagents were diluted 1:150 or 1:300 and the Cistron reagents were diluted 1:300 in PBS for subsequent experiments. An avidin-biotin immunoperoxidase kit that identifies rabbit IgG (Zymed, San Francisco, CA) was used to detect binding of the primary reagents. The peroxidase substrate was 3-amino-9-ethylcarbazole in N,Ndimethylformamide, which yields a red coloration to positive cells. Normal rabbit serum used to control for nonspecific binding of the developing reagents was purchased from Sigma, St. Louis, MO and normal human serum was obtained from laboratory volunteers.

Immunocytochemical staining procedures Paraffin was removed from the tissue sections with Histoclear (National Diagnostics, Manville, N J) and the sections were dehydrated in a series of graded alcohols. After rehydration in PBS, immunohistochemical stains were performed as described in the Zymed kit directions except for the following modifications: incubations of primary antibodies and equivalent concentrations of the normal rabbit serum were for 2 h at 37°C; the biotinylated antirabbit IgG reagent contained 20% heat-inactivated normal human serum to prevent crossreactivity with endogenous IgG and incubations with this component were for 30 min at room temperature. Endogenous peroxidase was blocked by using 0.02% H202 in methanol. The tissue sections were counterstained with Gill's hematoxylin. Results

As stated in the Materials and Methods, three samples each of first trimester placenta, term placenta and term extraplacental membranes were

260 TABLE 1 Summary of immunocytochemical stains for IL-Ia and IL-I/3 a Anti-IL- lct(l)/anti-IL- l/a (C)

Anti-IL- l/3(I)/anti-IL- I/~(C)

First trimester placenta Trophoblast Stromal cells Maternal blood Fetal blood

++/++ ++/++ +/+ 0/0

+/+ 0/0 ++/++ +/0

Term placenta Trophoblast Stromal cells Maternal blood Fetal blood

+/+ ++/++ +/+ 0/0

+/+ 0/0 ++/++ ++/0

Term membranes Trophoblast Stromal cells Maternal ceils

+/+ ++/++ +/+

0/0 0/0 ++/0

aRelative staining intensities are indicated as follows: 0, no staining; +, light staining; ++, intense staining. See text for further descriptions of distributions.

tested. While there were variations within and among the samples, general patterns were established. These are described in the paragraphs below and summarized in Table 1.

Localization of IL-la Figures 1A and 1B show that in first trimester placentas, the anti-IL-lot reagents stained syncytiotrophoblast and cytotrophoblastic cells as well as villous stromal cells. Although uniform cytoplasmic staining was characteristic of syncytiotrophoblast, discrete concentrations of IL-lc~ were present in both cytotrophoblastic cells underlying the syncytium and in cells randomly distributed through the villous stroma. Concentrations of protein Fig. 1. Immunocytochemical identification of IL-lot in placentas and extraplacental membranes with two polyclonal antibodies, anti-IL-h~(I) (A, C, E) and anti-IL-let(C) (B, D, F). (A) and (B) illustrate the staining patterns in first trimester placentas, where positive trophoblastic and stromal cells are marked with large and small arrows, respectively. (C) and (D) show staining patterns in term placenta. A large arrow marks positive syncytiotrophoblast and a small arrow marks an immunostained stromal cell. (E) and (F) show I L-l~t in term extraplacental membranes. Concentrations of the factor in fetal mesenchyme (FM) and the chorionic membrane (C) are marked with arrows. In some areas, positive cells were also found in the decidua (D). Lack of binding of normal rabbit serum to sections of the same tissues is shown in (G) first trimester placenta, (H) term placenta and (I) extraplacental membranes. Original magnifications, x 313.

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that were not clearly cell-associated were prominent in tissues stained with anti-IL-I or(I) whereas anti-IL-lot(C) was particularly effective in identifying discrete stromal cells as positive (Fig. 1B). Both reagents detected IL-lo~ in cytotrophoblastic columns emerging from the villi. Although some small round maternal blood cells contained IL-lc~, the staining intensity of these cells was low in comparison with ceils within the placental villi (not shown). Figures 1C and 1D show that in term placentas the same types of cells, trophoblast and stromal cells, contained IL-1 or. Intermittent stretches of syncytiotrophoblast were homogenously stained whereas granular staining was characteristic of the stromal cells, particularly in tissues stained with anti-ILlol(I). Anti-IL-lot(C) was again an effective reagent for identifying this protein in stromal cells (Fig. 1D). An occasional maternal blood cell also stained positively for IL-lc~. As shown in Figs. 1E and IF, IL-lot was present in fetal stromal cells and the acellular stroma and, to a lesser degree, the cytotrophoblastic layer of the extraplacental membranes. As in other tissues, deposits of IL-la were more readily identified with anti-IL-1 o4I) whereas discrete positive cells were more frequently demonstrated in tissues stained with anti-IL-lc~(C). In two of three samples, IL-lo~ positive cells were also identified in the adjacent decidua. No binding was observed when normal rabbit serum was substituted for the specific rabbit anti-human IL-lot reagents, as illustrated in Figs. 1G-I.

Localization of IL-If3 Figure 2 shows that in first trimester placentas, IL-1/3 was localized to cells in aggregates of maternal blood by anti-IL-1/3(I) (Fig. 2A). This reagent also recognized a few positive cells in fetal stem vessels. In contrast, anti-IL-lt3(C) (Fig. 2B) bound to concentrations of the protein in placental fibrin that did not appear invariably to be cell-associated. Although trophoblast in some villi stained lightly and homogenously with both reagents, stromal cells in the placental villi did not contain detectable IL-1/3 proteins. The same staining pattern was observed in term placentas, with antiIL-ll3(I) identifying round cells in both maternal blood and fetal stem Fig. 2. Immunocytochemical identification of IL-I/3 in placentas and extraplacental membranes with two polyclonal antibodies, anti-IL-lfl(I) (A, C, E) and anti-IL-lfl(C) (B, D, F). (A) and (B) show staining of first trimester placenta. Large arrows mark positive cells in maternal blood and small arrows mark immunoreactivity in fibrin associated with placental villi. (C) and (D) illustrate staining of term placenta. Large arrows point to positive cells in fetal stem vessels and small arrows to positive cells that are closely associated with placental villi. (E) and (F) show that IL-I~ was absent from fetal mesenchyme (FM). Positive cells in the chorion membrane and decidua are marked with large arrows and discrete concentration of the protein with small arrows. Lack of binding of normal rabbit serum to sections of the same tissues is shown in (G) first trimester placenta, (H) term placenta and (1) extraplacental membranes. Original magnifications, × 313.

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264

vessels (Fig. 2C) as positive and anti-IL-113(C) binding to concentrations of the protein in placental fibrin (Fig. 2D). In these late gestation tissues, the immunoreactive IL-113 recognized by anti-IL-1/3(C) was more clearly cellassociated. As in first trimester tissues, occasional stretches of trophoblast were lightly and homogenously stained with both anti-IL-1/3 reagents and villous stromal cells were negative. In term extraplacental membranes, cells in the mesenchymal stroma failed to bind the anti-IL-li3 reagents (Fig. 2E, 2F). Isolated positive cells in the chorionic membrane and decidua were recognized by anti-IL-1/3(I) but not by anti-IL-1/3(C) although the latter reagent bound to an occasional concentration of the protein (Fig. 2F). The morphology of the positive cells (Fig. 2E) indicated that they were maternal blood cells rather than decidual cells, which are usually less rounded. No binding was observed when normal rabbit serum was substituted for the specific rabbit anti-human IL-II3 reagents, as illustrated in Figs. 2G-I. Discussion

Several major points emerged from this investigation: (i) IL-lot and IL-1/3 are present in human placentas at both early and late stages of gestation, (ii) IL-lo~ predominates in extraembryonic tissues whereas IL-113 is found primarily in maternal and fetal blood cells, (iii) polyclonal reagents generated to recombinant IL-1 proteins do not yield identical staining patterns. Our observation that both species of IL-1 appear in placentas at early and late stages of gestation was in accord with previous reports of IL-lo~ and IL113in first trimester and term amniotic fluid where identifications were made by enzyme immunoassay (Tamatani et al., 1988; Tsunoda et al., 1990). IL-1 in placentas and extraplacental membranes might diffuse into the amniotic fluid although other fetal and maternal sources were not ruled out. Some of the protein may be inactive; Romero et al. (1989) failed to identify either species of IL-1 in early gestation amniotic fluid by using an IL-l-dependent cell line proliferation assay. A major finding in this study was that IL-lot and IL-1B are contained in different types of cells. IL-lot was particularly prominent in two types of placental villous cells, trophoblast and stromal cells. It is therefore of interest that IL-1 mRNA has been identified in cytotrophoblastic cells isolated from term placentas (Main et al., 1987) and that biologically active IL-1 has been identified as a product of macrophages isolated from term placentas (Flynn et al., 1982). As regards this latter cell type, macrophages populate the placental and extraplacental membrane stroma throughout gestation (Moskalewski et al., 1975; Fox, 1978; Hunt et al., 1984; Bulmer and Johnson, 1984; Lessin et al., 1988; Bulmer et al., 1988) and were therefore likely to have been among the IL-lc~ positive stromal cells identified in this study. The observations made thus far would therefore predict production of IL-la by

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both trophoblast and placental macrophages. The finding that IL-lot predominated in villous stromal cells while the alternate species, IL-1/3, predominated in fetal blood cells raises the intriguing possibility that migration of mononuclear phagocytes into the placental mesenchyme might induce a shift from IL-1/3 synthesis, the preferred species in blood monocytes, to ILlot synthesis. Blood cells and placental fibrin contained high levels of IL-1/3, as evaluated by staining intensity in comparison with other types of cells. Although IL-1/3 mRNA has been reported in extracts of first trimester decidua and term membranes that had been washed to remove blood, prompting the suggestion that IL-I/3 might be synthesized by non-leukocytes in these tissues (Kauma et al., 1990), our observations would suggest that much of the placental IL-1/3 originates in leukocytes. However, some trophoblast did contain IL-1/3 albeit at low levels in comparison with blood cells. As expected, the anti-IL-1/3 reagents stained blood cells more strongly than the anti-IL-lot reagents: IL-I/3 is preferentially synthesized by monocytes taken from the blood of adults (March et al., 1985); IL-1 synthesis is high in cord blood leukocytes throughout gestation (Dinarello et al., 1981); antibodies to IL-1/3 neutralize 80% of the IL-1 activity of cord blood mononuclear cells (Weatherstone and Rich, 1989). Our observation that IL-lot proteins were often concentrated in the cytoplasm whereas cell-associated IL-/3 was evenly distributed is in accordance with other reports on the intracellular distribution of these proteins. The cytoplasmic concentrations of IL-lot may have represented a storage step between synthesis/internalization and translocation of the growth factor and its receptor to the nucleus, a process that has been described in the murine T cell line EL-4 (Curtis et al., 1990). Homogenous cytoplasmic staining by the anti-IL-113 reagents was expected; immunoelectron microscopy has shown that IL-1/3 in stimulated human monocytes is dispersed within the cytoplasmic ground substance rather than associated with discrete cytoplasmic structures (Singer et al., 1988). Both similarities and differences were noted in the binding of the two sets of anti-IL-1 reagents. The reagents were alike in that both antibodies to ILlot were positive with trophoblast and villous stromal cells whereas anti-ILl/3 reagents recognized proteins in blood cells and fibrin external to the villi as well as in syncytiotrophoblast. However, the specific binding patterns of the individual reagents used in this study were not identical. Moreover, our results with polyclonal reagents differed somewhat from those obtained on a frozen section of term placenta tested with a set of monoclonal reagents (Taniguchi et al., 1991). As in this study, the monoclonal antibodies identified both species of IL-1 in syncytiotrophoblast. However, IL-1/3 rather than IL-lot was identified in stromal cells. Although we cannot be certain of the reasons for these differences, recognition of different biochemical forms

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is a reasonable possibility. IL-1 mRNA is translated into 31-34 kDa precursor molecules that are processed intracellularly into 17 kDa polypeptides (reviewed by Cavaillon and Haeffner-Cavaillon, 1990). Macrophages contain different forms of IL-1/3 precursor molecules (Gunther et al., 1991) and a unique high molecular weight form of IL-1/3 is found in amniotic fluid (Tamatani et al., 1988). The three sets of antibodies might therefore be useful in future explorations of IL-1 processing and storage in placental and other cells. Placental IL-1 could facilitate the development of embryonic immune responses to microbial invaders by enhancing lymphocyte responses and might also stimulate proliferation by trophoblast cells (Berkowitz et al., 1988; Hunt et al., 1989). Relevant to this latter potential function, Tartakovsky and Ben-Yair (1991) have shown that both IL-I~ and TNF-o~ restore fertility in mouse models of spontaneous resorption. Although IL-I often synergizes with TNF-o~ (Le and Vilcek, 1987), which is synthesized in syncytiotrophoblast (Chen et al., 1991), the protein inhibits TNF-induced increases in class I major histocompatibility antigen expression by rat endothelial cells (Leszczynski, 1990). If applicable to human placentas, this mechanism might account for the lack of class I antigens in the syncytiotrophoblast cell layer (Faulk and Temple, 1976), a major protective mechanism for the semiallogeneic fetus (reviewed by Hunt and Orr, 1992). Placental IL-1 could also stimulate interleukin-2 production (Lowenthal et al., 1986), a placental cytokine (Soubiran et al., 1987; Boehm et al., 1989) whose function is as yet unclear. It is of interest that two cytokines first identified as stimulators of lymphocyte proliferation, IL-1 and IL-2, are found in human placentas yet lymphoid nodules indicating clonal expansion are not found in adjacent maternal tissues, indicating that local immunoinhibitory factors such as prostaglandins (Lala et al., 1988) might predominate over these enhancing factors. New perspectives regarding the potential of inflammation-associated cytokines to modulate normal developmental processes are suggested by the identification of placental IL-1 in this and other studies and by our recent discovery of TNF-o~ mRNA and protein in placentas (Yelavarthi et al., 1991; Chen et al., 1991). Although both factors are commonly associated with inflammatory stimuli (Cavaillon and Haeffner-Cavaillon, 1990; Duncan et al., 1991), the placenta appears constitutively to produce these cytokines. It seems reasonable to propose, therefore, that in the unique environment of the pregnant uterus IL-1 and TNF-oL might function as growth and/or differentiation-inducing molecules, facilitating the dynamic developmental events that take place in this highly specialized organ.

Acknowledgements This study was supported by National Institutes of Health grant HD24212

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and by a grant from the Wesley Foundation, Wichita, KS (8805007A). The authors thank S. Gillis, Immunex Corp., for giving us the antibodies to IL-1 and D. Friesen for assistance in preparation of the figures. References Beresini, M.H., Lempert, M.J. and Epstein, L.B. (1988) Overlapping polypeptide induction in human fibroblasts in response to treatment with interferon-ct, interferon-% interleukin 1a, interleukin 1/3 and tumor necrosis factor. J. Immunol. 140, 485-493. Berkowitz, R.S., Hill, J.A., Kurtz, C.B. and Anderson, D.J. (1988) Effects of products of activated leukocytes (lymphokines and monokines) on the growth of malignant trophoblast cells in vitro. Am. J. Obstet. Gynecol. 158, 199-203. Boehm, K.D., Kelley, M.F., Ilan, J. and Ilan, J. (1989) The interleukin 2 gene is expressed in the syncytiotrophoblast of the human placenta. Proc. Natl. Acad. Sci. USA 86, 656-660. Bulmer, J.N. and Johnson, P.M. (1984) Macrophage populations in the human placenta and amniochorion. Clin. Exp. Immunol. 57, 393-403. Bulmer, J.N., Morrison, L. and Smith, J.C. (1988) Expression of class II MHC gene products by macrophages in human uteroplacental tissue. Immunology 63, 707-714. Cavaillon, J.-M. and Haeffner-Cavaillon, N. (1990) Signals involved in interleukin 1 synthesis and release by lipopolysaccharide-stimulated monocytes/macrophages. Cytokine 2, 313-329. Chen, H.-L., Yang, Y., Hu, X.-L., Yelavarthi, K.K., Fishback, J.L. and Hunt, J.S. (1991) Tumor necrosis factor-alpha mRNA and protein are present in human placental and uterine cells at early and late stages of gestation. Am. J. Pathol. 139, 327-335. Curtis, B.M., Widmer, M.B., deRoos, P. and Quarnstrom, E.E. (1990) IL-I and its receptor are translocated to the nucleus. J. Immunol. 144, 1295-1303. Dinarello, C.A. (1988) Biology of interleukin-1. FASEB J. 2, 108-115. Dinarello, C.A., Shparber, M., Kent, E.F. and Wolff, S.M. (1981) Production of leukocyte pyrogen from phagocytes of neonates. J. Infect. Dis. 144, 337-343. Dower, S.K. and Rudal, D.L. (1987) The interleukin-1 receptor. Immunol. Today 8, 46-51. Duncan, L.M., Meegan, L.S. and Unanue, E.R. (1991) IL-I gene expression in lymphoid tissues. J. Immunol. 146, 565-571. Elias, J.A., Gustilo, K., Baeder, W. and Freundlich, B. (1987) Synergistic stimulation of fibroblast prostaglandin production by recombinant interleukin I and tumor necrosis factor. J. lmmunol. 138, 3812-3816. Faulk, W.P. and Temple, A. (1976) Distribution of beta-2-microglobulin and HLA in chorionic villi of human placentas. Nature (London) 262, 799-802. Flynn, A., Finke, J.H. and Hilfiker, M.L. (1982) Placental mononuclear phagocytes as a source of interleukin-1. Science 218, 475-477. Fox, H. (1978) The development and structure of the placenta. Major Prob. Pathol. 7, 1-37. Gunther, C., Rollinghoff, M. and Beuscher, H.U. (1991) Formation of intrachain disulfide bonds gives rise to two different forms of the murine I1-1/3 precursor. J. Immunol. 146, 3025-3031. Hunt, J.S., King, C.R., Jr. and Wood, G.W. (1984) Evaluation of human chorionic trophoblasts and placental macrophages as stimulators of maternal lymphocyte proliferation in vitro. J. Reprod. Immunol. 6, 377-391. Hunt, J.S. and H.T. Orr. (1992) HLA and maternal-fetal recognition. FASEB J. 6, 2344-2348. Hunt, J.S., Soares, M.J., Lei, M.-G., Smith, R.N., Wheaton, D., Atherton, R.A. and Morrison, D.C. (1989) Products of lipopolysaccharide-activated macrophages (tumor necrosis factor-a, transforming growth factor-/3) but not lipopolysaccharide modify DNA synthesis by rat trophoblast cells exhibiting the 80 kDa lipopolysaccharide-binding protein. J. Immunol. 143, 1606-1613. Kauma, S., Matt, D., Strom, S., Eierman, D. and Turner, T. (1990) Interleukin-1/3, human leukocyte antigen HLA-DRa and transforming growth factor-/3 expression in endometrium, placenta, and placental membranes. Am. J. Obstet. Gynecol. 163, 1430-1437. Lala, P.K., Kennedy, T.G. and Parhar, R.S. (1988) Suppression of lymphocyte alloreactivity by early gestational human decidua. II. Characterization of the suppressor mechanisms. Cell. Immunol. 116, 411-422.

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Differential distribution of interleukin-1 alpha and interleukin-1 beta proteins in human placentas.

Interleukin-1 alpha (IL-1 alpha) and interleukin-1 beta (IL-1 beta) were identified in samples of first trimester and term placentas by immunocytochem...
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