Journal of Reproductive Immunology 83 (2009) 6064

Contents lists available at ScienceDirect

Journal of Reproductive Immunology

journal homepage: www.elsevier.com/locate/jreprimm

Progesterone in pregnancy; receptorligand interaction

and signaling pathways
Julia Szekeres-Bartho , Melinda Halasz, Tamas Palkovics
Department of Medical Microbiology and Immunology, Medical School, Pecs University, H-7624 Pecs, Szigeti ut 12, Hungary

a r t i c l e

i n f o

Article history:
Received 31 December 2008
Received in revised form 7 June 2009
Accepted 21 June 2009
Keywords:
Progesterone
Progesterone receptor
Progesterone target genes

a b s t r a c t
Progesterone is indispensable in creating a suitable endometrial environment for implantation, and also for the maintenance of pregnancy. Successful pregnancy depends on an
appropriate maternal immune response to the fetus. Along with its endocrine effects,
progesterone also acts as an immunosteroid, by contributing to the establishment of
a pregnancy protective immune milieu. Progesterone plays a role in uterine homing of
NK cells and upregulates HLA-G gene expression, the ligand for NK inhibitory and activating receptors. At high concentrations, progesterone is a potent inducer of Th2-type
cytokines as well as of LIF and M-CSF production by T cells. A protein called progesteroneinduced blocking factor (PIBF), by inducing a Th2-dominant cytokine production mediates
the immunological effects of progesterone. PIBF binds to a novel type of the IL-4 receptor
and signals via the Jak/STAT pathway, to induce a number of genes, that not only affect the
immune response, but might also play a role in trophoblast invasiveness.
2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Progesterone is critical for the establishment and for
the maintenance of pregnancy, as it regulates menstrual
bleeding, tissue repair and regeneration, inammation,
angiogenesis, and in late pregnancy, by interfering with
arachidonic acid metabolism it contributes to uterine quiescence. Besides its effects on the uterus, progesterone
mediates interactions between the endocrine and immune
systems, in order to create a favorable immunological
environment for the fetus. Progesterone has been shown
to; block mitogen-stimulated lymphocyte proliferation,
prolong allograft survival, modulate antibody production,
decrease the oxidative burst of monocytes, reduce the production of proinammatory cytokines by macrophages in
response to bacterial products and act on the cytokine pattern during pregnancy (reviewed by Beagley and Gockel,
2003). This review aims to discuss the signaling pathways

Corresponding author. Tel.: +36 72 536 262; fax: +36 72 536 253.
E-mail address: szjuli@main.pote.hu (J. Szekeres-Bartho).
0165-0378/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jri.2009.06.262

via which progesterone contributes to the success of pregnancy.

2. The immunological effects of progesterone in
pregnancy
Progesterone affects the materno-fetal immunological relationship at several levels. While a Th2-dominant
immune response is favorable for successful pregnancy, at
the same time, intrauterine infections (mostly by intracellular pathogens) also need to be handled by the maternal
immune system.
Uterine dendritic cells (DCs) are the key players in
directing the response to tolerance induction when harmless antigens are exposed, or alternatively; initiating a
robust immune response to pathogens (Kmmerer et al.,
2000). Progesterone favors the induction of the semimature tolerogenic DCs, and inhibits the activity of mature
DCs which can generate proinammatory responses (Liang
et al., 2006).
In rodents and humans, uterine NK cells play an
important role in creating a suitable environment for

J. Szekeres-Bartho et al. / Journal of Reproductive Immunology 83 (2009) 6064

the establishment of pregnancy (King et al., 1998). Uterine NK cells accumulate in the endometrium during
estrus and proestrus in rodents and during the luteal
phase in women as well as in early pregnancy at sites
where fetal trophoblast inltrates the decidua (Van den
Heuvel et al., 2005). Progesterone plays a role in uterine homing of NK cells by promoting NK cell interactions
with the endothelium (Van den Heuvel et al., 2005).
NK cell migration to the endometrium is supported
by progesterone-induced specic endometrial production of chemokines. Progesterone upregulates stromal cell
CXCL10/IP-10, CX3CL1/Fractalkine and CCL2/MCP-1 mRNA
expression, which results in a higher migratory ability of
peripheral pregnancy NK cells (Carlino et al., 2008).
In spite of their high perforin content, spontaneous cytotoxic activity of decidual NK cells is low (Crnic et al., 2007).
Progesterone increases IL-15 production by endometrial
stromal cells (Okada et al., 2000). Human decidual NK cells
express the IL-15 receptor and in response to IL-15 proliferate and augment their cytolytic activity against K562 cells
(Verma et al., 2000). Progesterone upregulates HLA-G gene
expression (Yie et al., 2006). Increased expression of HLAG, the ligand for NK inhibitory and activating receptors,
controls NK activity in the presence of progesterone.
Several studies show that a Th2-dominant cytokine
pattern favors normal pregnancy, while excessive production of Th1-associated cytokines leads to termination of
pregnancy (Raghupathy, 1997). Progesterone affects the
differentiation of resting human peripheral blood T cells
into Th2-like clones (Piccinni et al., 1995). Some of the
immunological effects of progesterone are mediated by the
progesterone-induced blocking factor (PIBF) (Polgar et al.,
2003), which by signaling via a novel form of the IL-4 receptor (Kozma et al., 2006), induces a Th2-dominant cytokine
response, including production of IL-3, IL-4, and IL-10
(Szekeres-Bartho and Wegmann, 1996). Neutralization of
endogenous PIBF activity in pregnant mice by specic
antibody terminates pregnancy, increases splenic NK cell
activity, reduces the synthesis of IL-10, and increases that
of IFN (Szekeres-Bartho et al., 1996). PIBF blocks upregulation of perforin expression in decidual lymphocytes in
the presence of adherent cells and inhibits NK cell cytotoxicity by blocking granule exocytosis without interfering
with target conjugation (Laskarin et al., 1999), which might
at least partly account for the low lytic activity of decidual
NK cells.
The hypothesis that Th1/Th2 skewing underlies successful pregnancy stems from observations on peripheral
blood lymphocytes. However, at different stages of gestation practically all cytokines have been shown to be
expressed in the decidua (Vince and Johnson, 1996) and
at least in mice, Th1 cytokines are not necessarily detrimental. Some of them (e.g., LIF, IL-11 and IFN) are even
needed for implantation of the mouse blastocyst (Stewart
et al., 1992; Bilinski et al., 1998; Ashkar et al., 2000).
3. Progesterone receptors
The above effects of progesterone depend on the
availability of progesterone receptors that act as nuclear
transcription factors, but also as modulators of cell sig-

61

naling pathways. The genomic actions of progesterone

are mediated by two intracellular receptors, progesterone
receptor A (PR-A) and progesterone receptor B (PR-B),
which are both members of the nuclear receptor superfamily (Li and OMalley, 2003). A third isoform, PR-C is an
N-terminally truncated form of PR-A and PR-B (Wei et al.,
1996) which serves as a decoy by modulating transcriptional activity of PR-A and PR-B. PR-A differs from PR-B
by the absence of the rst 123165 amino acids at the Nterminus. The reproductive phenotypes of PR-A and PR-B
gene knock out (KO) mice suggest that the two types of
receptors mediate distinct functions (Mulac-Jericevic et al.,
2000). Progesterone induced activation of PR-A is required
for implantation and decidualization, while selective ablation of PR-B knock out (PRBKO) has no uterine phenotype,
but results in reduced mammary gland morphogenesis.
Recent evidence suggests a role for PR-C in parturition
(Condon et al., 2006).
Progesterone receptors (PRs) have been demonstrated
in peripheral blood mononuclear cells and peripheral blood
T cells of pregnant women (Szekeres-Bartho et al., 2001).
Peripheral blood NK cells of pregnant women have been
shown to express both classical PR isoforms (Arruvito et
al., 2008). In line with this, RU486 treatment signicantly
augments NK cell cytolytic activity in vitro and this can
be reversed by treatment of NK cells with progesterone
(Hansen et al., 1992). Puried decidual NK cells do not
express PRs (Henderson et al., 2003), nevertheless progesterone could act on these cells through glucocorticoid
receptors (Henderson et al., 2003), putative membrane
receptors or calcium-activated K+ channels (Chien et al.,
2007).
Rapid non-genomic actions of progesterone are
attributed to recently described membrane receptors and
to progesterone receptor membrane component 1. The
membrane receptors are directly coupled to G proteins
and downregulate adenyl cyclase activity. They have been
implicated in progesterone regulation of uterine function
in humans, while the progesterone receptor membrane
component 1 mediates the antiapoptotic affects of progesterone (Thomas, 2008). Recent ndings suggest that
progesterone might act directly through a membrane
receptor to cause suppression of T cell activation during
pregnancy (Chien et al., 2007).
4. Target gene activation by PR
PRs are activated either by progesterone or in the
absence of progesterone by interaction with other signaling
pathways. During ligand-dependent activation, the inactive form of the receptor is localized in the cytoplasm
in complex with immunophilins and heat shock proteins. Upon progesterone binding, the receptor is released
from the complex, undergoes a conformational change
and translocates to the nucleus, to activate transcription.
Here a variety of co-regulators, including members of the
p160/SRC (steroid receptor coactivator) family, CBP/p300,
and ASC-2, the ubiquitin ligase E6-AP and ATP-dependent
chromatin remodeling complexes (SWI/SNF) form a link
between the activated receptor and the transcription
complex and enhance or downregulate transcriptional

62

J. Szekeres-Bartho et al. / Journal of Reproductive Immunology 83 (2009) 6064

activation (Mani, 2006). Alternatively, PR can be activated in a ligand-independent way, when it becomes
phosphorylated by activated kinases (cAMP-dependent
protein kinase, cyclin-dependent kinase-2) following an
interaction with other signal transduction pathways. The
phosphorylated receptor than moves to the nucleus and
induces target genes. The PR can also activate transcription
by directly activating signaling pathways through interaction with Src kinase. Src is involved in several pathways
(e.g., the Src/Ras/Raf/MAP kinase cascade), which are critical for proliferation, differentiation, and angiogenesis, and
thus needed for decidualization (Shimizu et al., 2005).
5. Progesterone target genes
Most of the progesterone-activated genes that have
been identied so far play a key role in implantation and
decidualization. Indian Hedgehog is a member of the Hedgehog family of diffusible morphogens which regulate cell
proliferation and differentiation. Indian Hedgehog mediates
the communication between the uterine epithelium and
stroma in the peri-implantation period (Takamoto et al.,
2002).
Bone morphogenetic protein 2 (Bmp2) a member of the
BMP family of morphogens is expressed in the uterine
stroma at the site of attachment. Female Bmp2 KO mice are
infertile due to decidualization defects and implantation
failure. Bmp2 activates other genes involved in endometrial development. Wnt4, a member of the Wnt family of
morphogens, is a downstream target of Bmp2, while Bmp2
acts upstream on cyclooxygenase 2 (Cox-2) (Lee et al., 2007).
The expression of Wnt4 increases with decidualization in
both mouse and human uterus. Cox-2 KO female mice have
implantation failure and demonstrate a lack of decidual
reaction.
The progesterone-activated cell cycle regulatory genes
p27 and p53 play a role in both the establishment of a
receptive endometrium and in the control of trophoblast
invasion. P27 KO mice have an implantation defect, though
the decidual response is normal. The tumor suppressor
gene p53 seems to play a role in trophoblast invasion.
Phosphorylated p53 acts as an onco-suppressor by inducing either cell cycle arrest or apoptosis. In invasive tumors
the p53 gene is inactivated, or the p53 pathway is otherwise defective. In the cytotrophoblast a non-functional
form of p53 is localized in the cytoplasm, suggesting its role
in trophoblast invasiveness (Cohen et al., 2008). Another
function of p53 has been shown to be the control of LIF
expression, which is necessary for embryo implantation.
Among the progesterone-regulated genes Hox-A10,
Hox-A11 (both members of homeobox gene family),
galectin-1 and PIBF are the most relevant for the
feto-maternal immunological interaction. Hoxa-10 is an
important regulator of two critical events in implantation:
stromal cell proliferation and local immunosuppression.
Hox-A10 expression persists through day 4.5 to day 7.5 in
the developing decidua (Satokata et al., 1995) and mediates the progesterone-stimulated proliferation of uterine
stromal cells (Yao et al., 2003). Hoxa-10 mutants express
a stromal cell proliferation defect that is accompanied
by altered expression of two cyclin-dependent kinase

inhibitor genes, p57 and p15 (Yao et al., 2003). Female

Hox-A10 KO mice are infertile (Satokata et al., 1995) due
to implantation disorders and poor decidualization. While
the expression of several implantation genes is normal in
these mice, PGE2 receptors as well as Cox-2 are downregulated. Hox-A10 deciency in mice leads to severe
local immunological disturbances, characterized by a polyclonal proliferation of T cells in the peri-implantation
uterus (Yao et al., 2003). Hox-A10 deciency in mice alters
region-specic gene expression and compromises NK cell
differentiation, but not trafcking of NK precursor cells
during decidualization (Rahman et al., 2006).
In the uterus Gal-1 expression is restricted to the
endometrium and increases signicantly in the late secretory phase endometrium and in decidual tissue (Maquoi et
al., 1997).
The expression of Gal-1 is downregulated on placental
villous tissues from patients with spontaneous miscarriages (Liu et al., 2006). A growing body of evidence
indicates that Gal-1 functions as a homeostatic agent
by modulating innate and adaptative immune responses.
Gal-1 induces the inhibition of cell growth and cell
cycle arrest (Rabinovich et al., 2002) Gal-1 also suppresses the secretion of the proinammatory cytokine
interleukin-2 (IL-2) (Rabinovich et al., 1999) and favors
the secretion of the anti-inammatory cytokine IL-10. In
early pregnancy, progesterone-regulated Gal-1 (Blois et al.,
2007) induces immature DCs in the decidua (Kmmerer
et al., 2000). Furthermore, Gal-1-decient mice show
higher rates of fetal loss compared with wild-type mice
in allogeneic matings (Blois et al., 2007). Treatment
with recombinant Gal-1 prevents fetal loss and restores
tolerance through multiple mechanisms, including the
induction of tolerogenic DCs, which in turn promotes
the expansion of IL-10-secreting regulatory T (Treg) cells
in vivo. Progesterone-treatment increases the levels of
Gal-1 expression in the myometria and deciduas of stresschallenged pregnancies on gestational day 7.5, suggesting
the existence of a progesterone-mediated mechanism that
regulates Gal-1 expression at the feto-maternal interface
(Blois et al., 2007). Reciprocally, Gal-1 treatment prevents
the stress-induced decrease in progesterone and PIBF and
increases the concentration of these hormones in sera to
levels that are signicantly higher than those found during
normal gestation in mice (Blois et al., 2007).
PIBF is a progesterone target gene in pregnancy lymphocytes. PIBF signals via the Jak1/Stat6 pathway (Kozma
et al., 2006) and regulates a number of genes including
cytokines, and those involved in apoptosis, cell cycle regulation, migration and invasion (unpublished).
6. Conclusions
In humans, progesterone is a crucial regulator of the
events leading to the establishment and maintenance
of pregnancy. Acting through its receptor, progesterone
activates genes that contribute to cell cycle regulation,
proliferation, differentiation and invasion, all needed to
prepare the endometrium for implantation. Furthermore,
progesterone targets are involved in creating a suitable
cytokine environment for the developing fetus. To date

J. Szekeres-Bartho et al. / Journal of Reproductive Immunology 83 (2009) 6064

several mediators and signaling pathways have been

elucidated, yet neither the receptors nor the signal transduction pathways that mediate the action of progesterone
have been completely dened. Further identication of
progesterone-regulated molecular pathways might provide new data that could be used for improving the
treatment of infertility.
Acknowledgements
This work was supported by grants from Hungarian
Natl Research Fund (OTKA T031737), Hungarian Ministry
of Health (ETT 045/2003), and by the EU (European Network of Excellence on Embryo Implantation Control Contr.
No. 512040).
References
Ashkar, A.A., Di Santo, J.P., Croy, B.A., 2000. Interferon gamma contributes
to initiation of uterine vascular modication, decidual integrity, and
uterine natural killer cell maturation during normal murine pregnancy. J. Exp. Med. 192, 259270.
Arruvito, L., Giulianelli, S., Flores, A.C., Paladino, N., Barboza, M., Lanari,
C., Fainboim, L., 2008. NK cells expressing a progesterone receptor
are susceptible to progesterone-induced apoptosis. J. Immunol. 180,
57465753.
Beagley, K.W., Gockel, C.M., 2003. Regulation of innate and adaptive
immunity by the female sex hormones oestradiol and progesterone.
FEMS Immunol. Med. Microbiol. 38, 1322.
Bilinski, P., Roopenian, D., Gossler, A., 1998. Maternal IL-11Ralpha function
is required for normal decidua and fetoplacental development in mice.
Genes Dev. 12, 22342243.
Blois, S., Ilarregui, J.M., Tometten, M., Garcia, M., Orsal, A.F., Toscano, M.,
Handjiski, B., Tirado, I., Markert, U.R., Poirier, F., Szekeres-Bartho, J.,
Rabinovich, G., Arck, P., 2007. A pivotal role for galectin-1 in fetal
tolerance. Nat. Med. 13, 14501457.
Carlino, C., Stabile, H., Morrone, S., Bulla, R., Soriani, A., Agostinis, C., Bossi,
F., Mocci, C., Sarazani, F., Tedesco, F., Santoni, A., Gismondi, A., 2008.
Recruitment of circulating NK cells through decidual tissues: a possible mechanism controlling NK cell accumulation in the uterus during
early pregnancy. Blood 111, 31083115.
Chien, E.J., Liao, C.F., Chang, C.P., Pu, H.F., Lu, L.M., Shie, M.C., Hsieh, D.J.,
Hsu, M.T., 2007. The non-genomic effects on Na(+)/H(+)-exchange 1
by progesterone and 20alpha-hydroxyprogesterone in human T cells.
J. Cell. Physiol. 211, 544550.
Cohen, M., Wuillemin, C., Irion, O., Bischof, P., 2008. Regulation of MMP9 by p53 in rst trimester cytotrophoblastic cells. Hum. Reprod. 23,
22732281.
Condon, J.C., Hardy, D.B., Kovaric, K., Mendelson, C.R., 2006. Upregulation
of the progesterone receptor (PR)-C isoform in laboring myometrium
by activation of NF-{kappa}B may contribute to the onset of labor
through inhibition of PR function. Mol. Endocrinol. 20, 764775.
Crnic, T.B., Laskarin, G., Frankovic, K.J., Tokmadzic, V.S., Strobo, N.,
Bedenicki, I., Le Bouteiller, P., Tabiasco, J., Rukavina, D., 2007. Early
pregnancy decidual lymphocytes beside perforin use Fas ligand (FasL)
mediated cytotoxicity. J. Reprod. Immunol. 73, 108117.
Hansen, K.A., Opsahl, M.S., Nieman, L.K., Baker Jr., J.R., Klein, T.A., 1992.
Natural killer cell activity from pregnant subjects is modulated by RU
486. Am. J. Obstet. Gynecol. 166, 8790.
Henderson, T.A., Saunders, P.T., Moffet-King, A., Grrome, N.O., Critchley,
H.O., 2003. Steroid receptor expression in uterine natural killer cells.
J. Clin. Endocrinol. Metabol. 88, 440449.
Kmmerer, U., Schoppet, M., McLellan, A.D., Kapp, M., Huppertz, H.I.,
Kampgen, E., Dietl, J., 2000. Human decidua contains potent immunostimulary CD83+ dendritic cells. Am. J. Pathol. 157, 159169.
King, A., Burrows, T., Verma, S., Hiby, S., Loke, Y.W., 1998. Human uterine
lymphocytes. Hum. Reprod. Update 4, 480485.
Kozma, N., Halasz, M., Polgar, B., Poehlmann, T.G., Markert, U.R., Palkovics,
T., Keszei, M., Kiss, K., Szeberenyi, J., Par, G., Grama, L., Szekeres-Bartho,
J., 2006. PIBF activates STAT6 via binding to a novel IL-4 receptor. J.
Immunol. 176, 819826.
Laskarin, G., Strbo, N., Sotosek, V., Podack, R.E., Szekeres-Bartho, J., Rukavina, D., 1999. Progesterone directly and indirectly affects perforin
expression in cytolytic cells. Am. J. Reprod. Immunol. 42, 312320.

63

Lee, K.Y., Jeong, J.W., Wang, J., Ma, L., Martin, J.F., Tsai, S.Y., Lydon, J.P.,
DeMayo, F.J., 2007. Bmp2 is critical for the murine uterine decidual
response. Mol. Cell. Biol. 27, 54685478.
Li, X., OMalley, B.W., 2003. Unfolding the action of progesterone receptors.
J. Biol. Chem. 278, 3926139264.
Liang, J., Sun, L., Wang, Q., Hou, Y., 2006. Progesterone regulates mouse
dendritic cells differentiation and maturation. Int. Immunopharmacol.
6, 830838.
Liu, A.X., Jin, F., Zhang, W.W., Zhou, T.H., Zhou, C.Y., Yao, W.M., Qian,
Y.L., Huang, H.F., 2006. Proteomic analysis on the alteration of protein expression in the placental villous tissue of early pregnancy loss.
Biol. Reprod. 75, 414420.
Mani, S.K., 2006. Signaling mechanisms in progesterone-neurotransmitter
interactions. Neuroscience 138, 773781.
Maquoi, E., van den Brule, F.A., Castronovo, V., Foidart, J.M., 1997. Changes
in the distribution pattern of galectin-1 and galectin-3 in human placenta correlates with the differentiation pathways of trophoblasts.
Placenta 18, 433439.
Mulac-Jericevic, B., Mullinax, R.A., DeMayo, F.J., Lydon, J.P., Conneely, O.M.,
2000. Subgroup of reproductive functions of progesterone mediated
by progesterone receptor-B isoform. Science 289, 17511754.
Okada, H., Nakajima, T., Sanezumi, M., Ikuta, A., Yasuda, K., Kanzaki, H.,
2000. Progesterone enhances interleukin-15 production in human
endometrial stromal cells in vitro. J. Clin. Endocrinol. Metabol. 85,
47654770.
Piccinni, M.-P., Giudizi, M.G., Biagiotti, R., Beloni, L., Giannarini, L., Sampognaro, S., Parronchi, P., Manetti, R., Livi, C., Romagnani, S., Maggi,
E., 1995. Progesterone favors the development of human T helper
cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cells clones.
J. Immunol. 155, 128133.
Polgar, B., Kispal, G., Lachmann, M., Paar, C., Nagy, E., Csere, P.,
Miko, E., Szereday, L., Varga, P., Szekeres-Bartho, J., 2003. Molecular cloning and immunologic characterization of a novel cDNA
coding for progesterone-induced blocking factor. J. Immunol. 171,
59565963.
Rabinovich, G.A., Ramhorst, R.E., Rubinstein, N., Corigliano, A., Daroqui, M.C., Kier-Joffe, E.B., Fainboim, L., 2002. Induction of allogenic
T-cell hyporesponsiveness by galectin-1-mediated apoptotic and
non-apoptotic mechanisms. Cell Death Differ. 9, 661670.
Rabinovich, G.A., Ariel, A., Hershkoviz, R., Hirabayashi, J., Kasai, K.I.,
Lider, O., 1999. Specic inhibition of T-cell adhesion to extracellular
matrix and proinammatory cytokine secretion by human recombinant galectin-1. Immunology 97, 100106.
Raghupathy, R., 1997. Th-1 type immunity is incompatible with successful
pregnancy. Immunol. Today 18, 478482.
Rahman, M.A., Li, M., Li, P., Wang, H., Dey, S.K., Das, S.K., 2006. Hoxa-10
deciency alters region-specic gene expression and perturbs differentiation of natural killer cells during decidualization. Dev. Biol. 290,
105117.
Satokata, I., Benson, G., Maas, R., 1995. Sexually dimorphic sterility phenotypes in Hoxa10-decient mice. Nature 374, 460463.
Shimizu, A., Maruyama, T., Tamaki, K., Uchida, H., Asada, H., Yoshimura,
Y., 2005. Impairment of decidualization in SRC-decient mice. Biol.
Reprod. 73, 12191227.
Stewart, C.L., Kaspar, P., Brunet, L.J., Bhatt, H., Gadi, I., Kontgen, F.,
Abbondazo, S.J., 1992. Blastocyst implantation depends on maternal
expression of leukaemia inhibitory factor. Nature 359, 7679.
Szekeres-Bartho, J., Wegmann, T.G., 1996. A progesterone-dependent
immunomodulatory protein alters the Th1/Th2 balance. J. Reprod.
Immunol. 31, 8195.
Szekeres-Bartho, J., Faust, Zs., Varga, P., Szereday, L., Kelemen, K., 1996. The
immunological pregnancy protective effect of progesterone is manifested via controlling cytokine production. Am. J. Reprod. Immunol.
35, 348351.
Szekeres-Bartho, J., Barakonyi, A., Miko, E., Polgar, B., Palkovics, T., 2001.
The role of / T cells in the feto-maternal relationship. Semin.
Immunol. 13, 229233.
Takamoto, N., Zhao, B., Tsai, S.Y., Demayo, F.J., 2002. Identication of Indian
Hedgehog as a progesterone-responsive gene in the murine uterus.
Mol. Endocrinol. 16, 23382348.
Thomas, P., 2008. Characteristics of membrane progestin receptor
alpha (mPR) and progesterone membrane receptor component 1
(PGMRC1) and their roles in mediating rapid progestin actions. Front.
Neuroendocrinol. 29, 292312.
Van den Heuvel, M.J., Chantakru, S., Xumei, X., Evans, E.E., Tekpetey, F.,
Mote, P.A., Clarke, C.L., Croy, B.A., 2005. Trafcking of circulating proNK cells to the decidualizing uterus: regulatory mechanisms in the
mouse and human. Immunol. Invest. 34, 273293.

64

J. Szekeres-Bartho et al. / Journal of Reproductive Immunology 83 (2009) 6064

Verma, S., Hiby, S.E., Loke, Y.W., King, A., 2000. Human decidual natural killer cells express the receptor for and respond to the cytokine
interleukin 15. Biol. Reprod. 62, 959968.
Vince, G.S., Johnson, P.M., 1996. Is there a Th2 bias in human pregnancy?
J. Reprod. Immunol. 32, 101104.
Wei, L.L., Hawkins, P., Baker, C., Norris, B., Sheridan, L.P., Quinn, P.G., 1996.
An amino-terminal truncated progesterone receptor isoform, PRc,
enhances progestin-induced transcriptional activity. Mol. Endocrinol.
10, 13791387.

Yao, M.W., Lim, H., Schust, D.J., Choe, S.E., Farago, A., Ding, Y.,
Michaud, S., Church, G.M., Maas, R.L., 2003. Gene expression proling reveals progesterone-mediated cell cycle and immunoregulatory
roles of Hoxa-10 in the preimplantation uterus. Mol. Endocrinol. 17,
610627.
Yie, S.M., Xiao, R., Librach, C.L., 2006. Progesterone regulates HLA-G gene
expression through a novel progesterone response element. Hum.
Reprod. 21, 25382544.