Human Reproduction Update Advance Access originally published online on December 6, 2007
Human Reproduction Update 2008 14(2):179-192; doi:10.1093/humupd/dmm042
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Cytokine knockouts in reproduction: the use of gene ablation to dissect roles of cytokines in reproductive biology
1 Discipline of Obstetrics and Gynaecology, Research Centre for Reproductive Health, University of Adelaide, South Australia 5005, Australia 2 Maternal and Fetal Health Research Group, University of Manchester, St Mary’s Hospital, Manchester, UK
3 Correspondence address. E-mail: wendy.ingman{at}adelaide.edu.au
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Abstract |
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Cytokines play many diverse and important roles in reproductive biology, and dissecting the complex interactions between these proteins and the different reproductive organs is a difficult task. One approach is to use gene ablation, or ‘knockout’, to analyse the effect of deletion of a single cytokine on mouse reproductive function. This review summarizes the essential roles of cytokines in reproductive biology that have been revealed by gene knockout studies, including development and regulation of the hypothalamo-pituitary-gondal axis, ovarian folliculogenesis, implantation and immune system modulation during pregnancy. However, successful utilization of this approach must consider the caveats associated with gene ablation studies, e.g. embryonic lethality, systemic effects of cytokine ablation on local reproductive processes and the limited exposure to pathogens in mice housed in laboratory conditions. New sophisticated technology that temporally or spatially regulates gene ablation can overcome some of these limitations. Discoveries on the roles of cytokines in reproductive function uncovered by gene ablation studies can now be applied to improve in vitro fertilization for infertile couples and in the development of contraceptive therapies.
Key words: cytokines / gene ablation / animal model / IVF / contraception
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Introduction |
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Cytokines are soluble protein signalling molecules that interact with cells of the immune system. These include the interleukins (ILs), colony stimulating factors (CSFs) and tumour necrosis factor (TNF) families. Growing understanding of the cytokine-like actions of many growth factors [e.g. transforming growth factors (TGFs), activin] and endocrine hormones (e.g. prolactin, growth hormone), has broadened the range of factors we now consider as cytokines. The functions of cytokines are far from restricted to immune cell regulation. Cytokines are also critical to the success of the reproductive process, through direct actions on reproductive cells including germ cells, the embryo, non-haematopoietic cells in the gonads and uterus, and indirectly through the promotion of an immunologically receptive environment for the production of gametes, implantation and development of the conceptus and parturition. Understanding which cytokines are involved in the reproductive process, and how, is critical to the design of therapeutics which aim to correct reproductive pathologies of immune origin, including some forms of infertility, endometriosis, recurrent spontaneous abortion, pre-eclampsia and preterm labour.
Without highly regulated immune responses, the ability to defend the organism against dangerous pathogens, while tolerating self and non-harmful pathogens and allowing reproduction of a genetically dissimilar offspring, is in jeopardy. Decisions regarding when to mount an immune response to a pathogen and what type of response is required are mediated by a complex array of cytokines, many with overlapping functions. It is generally not the presence or absence of any one cytokine that is responsible for the resultant immune response, rather the collective effect of what has become known as the ‘cytokine milieu’, or cytokine microenvironment surrounding the effector cell. Redundancy is therefore common amongst cytokines, and discovering which cytokines are most functionally significant in any given process is not a simple task.
Studies describing in vivo expression of cytokines and their receptors tell us which cytokines we should be investigating, and in vitro cell culture experiments inform on what role the cytokine might have. However, in vivo experimentation involving the addition or removal of the cytokine is necessary to understand the impact this cytokine has on physiology and pathology. Commonly, mice are used for initial in vivo experimentation, for a variety of reasons, including the ease at which the mouse genome can be manipulated by the selective deletion or addition of genes. This review examines the impact of ‘knockout’ technology on our understanding of the role of cytokines in reproductive biology, highlighting the problems which are encountered by this type of approach, how these problems can be overcome and opportunities for future applications of this technology.
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The current literature on the roles of cytokines in reproductive biology was searched on Entrez Pubmed (http://www.ncbi.nlm.nih.gov/sites/entrez) using combinations of the following keywords: cytokine, reproduction, fertility, null, knockout, mouse, immune, IL, transforming-growth-factor, colony-stimulating-factor, tumour-necrosis-factor, leukaemia-inhibitory-factor, activin, suppressors-of-cytokine-signalling, hormone, ovary, testis, pregnancy, implantation, endometrium, decidualization and parturition.
Introduction to the roles of cytokines in reproductive function
The following is a summary of the major roles of cytokines within reproductive tissues. It is not intended to be a comprehensive review of all cytokines involved in reproductive function, but aims to provide a framework for understanding the most significant pathways and processes currently recognized to be affected by cytokines.
Gonads
An array of cytokines are secreted by testicular cells. Through precise spatial and temporal expression, these cytokines facilitate many interactions within the testis, between Leydig cells, Sertoli cells and germ cells, regulating immune privilege, steroidogenesis and spermatogenesis (Hedger and Meinhardt, 2003
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The blood testis barrier divides the seminiferous tubule epithelium into a basal and adluminal compartment, and prevents direct contact between post-meiotic male germ cells and the systemic immune system (Xia et al., 2005). The blood testis barrier must physically restructure to allow the migration of maturing spermatocytes, and this is facilitated by TGF-β3 and TNF-
(Lui et al., 2001; Siu et al., 2003). However, immune privilege in the testis is not just physical isolation of germ cells, but a more complex system involving testicular macrophages and anti-inflammatory cytokines produced by non-immune cells in the testis (Fijak and Meinhardt, 2006).
The testis contains many immune cells. Macrophages comprise the majority of leukocytes in the testis, with mast cells and T lymphocytes also present (Wang et al., 1994). Testicular macrophages produce cytokines including IL-1 and -6, TNF- and granulocyte macrophage-CSF (GM-CSF) (Kern et al., 1995). Pro-inflammatory cytokines, TNF- and IL-1 produced by activated macrophages have inhibitory effects on Leydig cell testosterone synthesis (Calkins et al., 1990; Mauduit et al., 1992; Xiong and Hales, 1993) and are believed to repress reproductive behaviour in immune challenged rodents (Hales, 2002). Macrophages have also been shown to be critical for spermatocyte development, presumably by the production of cytokines that act on Leydig cells to promote testosterone synthesis, on Sertoli cells, and on the gamete itself (Hedger, 2002).
Less is known about how immune privilege manifests in the ovary. However, the mechanism is likely to involve an array of cytokines mediating different forms of immune tolerance and suppression. Many cytokines, including members of the TGF-β superfamily, IL-1β and TNF-, are an important part of cell–cell signalling in the ovary, between the oocyte and its surrounding somatic cells in the follicle, and in regulation of follicle survival and apoptosis (Kaipia and Hsuen, 1997; Bornstein et al., 2004; Knight and Glister, 2006). Macrophages in the ovary also secrete cytokines, including interferon-
(IFN-), TNF- and GM-CSF, which promote oocyte development, the production of progesterone by the corpus luteum and ovulation (Wu et al., 2004).
Endometrium
Menstruation is an inflammatory event involving the infiltration of large populations of neutrophils and macrophages, the activation of resident mast cells and up-regulation of matrix degrading proteases (Finn, 1986). Inflammatory chemokines, including IL-8, fractalkine and macrophage derived chemokine (MDC), are up-regulated in the endometrium premenstrually (Jones et al., 1997; Hannan et al., 2004; Jones et al., 2004). Leukocyte products (pro-inflammatory cytokines IL-1, TNF-, chemokines, prostaglandins and proteases) are likely to be instrumental in the focal initiation and amplification of endometrial inflammation and breakdown (Salamonsen and Lathbury, 2000). Re-epithelialization is complete within 48 h of the onset of bleeding, and occurs in the absence of estrogen (Ferenczy, 1976). To date, much of our understanding of endometrial repair is from extrapolation of wound healing studies, and many repair-promoting cytokines are expressed perimenstrually (activin A and B, TGF-β) (Jones et al., 2006). The endometrium repairs without scarring, similar to fetal wound healing, which has been postulated to involve subtle alterations in cytokine expression (including ILs: IL-6, IL-8, IL-10) (Salamonsen, 2003).
Decidualization is a necessary preparatory event for pregnancy and involves the differentiation of endometrial stromal cells and widespread tissue remodelling. An array of cytokines are produced and secreted from decidualizing cells, and indeed a number of decidual cell products facilitate decidualization of human endometrial stromal cells in vitro. IL-11, G-CSF and activin A promote decidualization, whereas TNF-, M-CSF and IL-1β inhibit this process (Inoue et al., 1994; Dimitriadis et al., 2005).
Pregnancy
Embryo development and implantation
Pre-implantation development occurs in a cytokine and growth factor-rich fluid, secreted by the epithelial cells of the Fallopian tube and uterus, many of which promote embryo development in vitro (Sargent et al., 1998; Sjoblom et al., 1999). Uterine gland products, including leukaemia inhibitory factor (LIF) and TGF-β have continued roles in early placental development (Hempstock et al., 2004). Development of the placental villous structure occurs in conjunction with invasion of the decidua by placental cytotrophoblast cells, which remodel decidual arteries to establish utero-placental circulation. There is accumulating evidence for critical interactions between immune cells, including uterine natural killer (uNK) cells, and cytotrophoblasts during vascular remodelling (Leonard et al., 2006). Suboptimal placentation contributes to pre-eclampsia, intrauterine growth retardation and pregnancy failure. Cytotrophoblast invasion of the decidua is regulated by a host of paracrine factors—including cytokines that act to either promote (IL-1, IL-6, IL-15, activin) or limit invasive potential (IL-10, TNF-, TGF-β) (Bischof et al., 2000, Dimitriadis et al., 2005).
Maternal immune responses during pregnancy
Pregnancy poses a significant challenge to the maternal immune system, which must protect both mother and fetus from pathogenic assault, and yet prevent immune-mediated rejection of the semi-allogeneic (genetically disparate) fetus. This has been the topic of much debate, notably since the description of the fetus as an allograft by Medawar (1953), which formulated the commonly held view of a generalized suppression or alteration of the maternal immune system to enable tolerance to be acquired to the fetus. The field was advanced by Wegmann in 1993, who proposed that pregnancy required a switch from an inflammatory T helper cell 1 (Th1) immune profile (e.g. TNF-, IFN-, IL-12, IL-2), towards a protective Th2 (e.g. IL-10, IL-4) profile (Wegmann et al., 1993). Despite some supporting evidence of a Th2 bias in pregnancy, over a decade of research has failed to confirm this simplistic hypothesis (reviewed by Chaouat et al., 2004). Indeed there is strong evidence for both a local intrauterine and systemic inflammatory response to pregnancy, involving increased immune trafficking and cytokine production at the implantation site in mice and humans (Robertson et al., 1997; Sharkey, 1998) and elevated levels of circulating pro-inflammatory cytokines (IL-6, IL-12 and TNF-) in sera of pregnant women (Sargent et al., 2006).
Despite waning support for a global Th2 bias in pregnancy, evidence for a role of T cells in maternal tolerance is gaining momentum. Regulatory T cells, involved in suppression of T cell responses, are found in increasing quantity in peripheral blood during pregnancy in mice and humans (Aluvihare et al., 2004; Somerset et al., 2004) and are necessary for allogeneic fetal survival (Aluvihare et al., 2004). At the maternal–fetal interface, T cell responses are suppressed by local secretion of indoleamine 2,3-dioxygenase, an enzyme that catabolizes the amino acid tryptophan, necessary for T cell proliferation (Munn et al., 1998). Again, this mechanism of T cell regulation is necessary for allogeneic but not syngeneic fetal survival.
There is a growing body of evidence to suggest that the specialized innate immune system within the uterus is particularly important for pregnancy success (Sargent et al., 2006). At the maternal–fetal interface, a number of placental and maternal strategies have been identified that appear to contribute to maternal tolerance to the conceptus. Importantly, from the moment of implantation, the embryo is protected from direct contact with maternal cells by the placenta. Placental cells evade immune surveillance by the maternal adaptive immune system, either by lacking cell surface expression of MHC class I antigens (villous syncytiotrophoblast) or by expression of a unique repertoire of non-classical non-polymorphic human leukocyte antigens (HLA), HLA-C, -E and -G (extravillous cytotrophoblast cells) (Ellis, 1990; King et al., 2000). The latter cell type invades the maternal decidua, and come into contact with the unique immunological environment comprising mainly uNK cells and macrophages (King et al., 1998). Communication between uNK cells and HLA-G, in particular, has been proposed to be a critical component of maternal acceptance of the semi-allogeneic embryo (Moffett-King, 2002).
At the same time as averting immune-mediated rejection, the maternal immune system must act to protect both the mother and the developing fetus against pathogens (bacterial, viral, fungal). Intrauterine infections (sexually transmitted and ascending vaginal infections) are potentially harmful to mother and fetus, and are a major cause of premature labour and maternal and neonatal morbidity. During pregnancy, the primary uterine mucosal defences are those of the innate immune system: NK cells, macrophages, dendritic cells and neutrophils, with a major supporting role by endometrial luminal epithelial cells (Wira et al., 2005). These secrete antimicrobials [β-defensins, secretory leukocyte protease inhibitor (SLPI)] that create a sterile environment (King et al., 2003), express Toll-like receptors (TLRs) that recognize foreign antigens, and are primed to secrete an array of cytokines (e.g. IL-6, TNF-, GM-CSF) and chemokines (e.g. IL-8, MCP-1), which serve to activate cells of the innate immune system (Wira et al., 2005).
There has been recent speculation concerning a more widespread role for the innate immune system, specifically for peripheral NK cells in pregnancy-specific immune responses. NK cells have been demonstrated to exhibit similar cytokine profiles to Th cells, with a proposed shift towards Th2-type responses in pregnancy (Sargent et al., 2006). This intriguing development suggests that despite growing knowledge of the complex cytokine networks at the maternal–fetal interfaces of pregnancy, we are far from understanding the intricate immune system balance required for pregnancy success.
Parturition
Myometrial quiescence and cervical competence are essential for maintaining pregnancy, and a number of anti-inflammatory mechanisms [e.g. progesterone suppression of inflammatory cytokines and mediators (Kelly, 1994)] are in place to prevent premature labour. These cytokine networks are reversed at term, allowing activation of a cascade of events inducing cervical ripening, myometrial contraction and parturition. Intrauterine bacterial infection is a major cause of preterm labour, stimulating local (fetal membrane and decidual) and systemic expression and release of pro-inflammatory cytokines (e.g. IL-1 and TNF-) (Park et al., 2005). There is evidence however for inherent differences in susceptibility of individuals to infection during pregnancy. A delicate balance between hypo- and hyper-responsiveness in the immune response to infection has been hypothesized (Simhan et al., 2003). Women with low capacity to respond to vaginal infection through the production of pro-inflammatory cytokines, IL-1β, IL-6 and IL-8, might have a more permissive environment for pathogens to flourish, and are at risk of ascending uterine infection and chorioamnionitis (Simhan et al., 2003). However, hyper-responsiveness to vaginal infection is suggested to also be detrimental to pregnancy, and elevated levels of IL-6 have been found to be a predictor of preterm labour (Wenstrom et al., 1998; Goepfert et al., 2001).
Conventionally, gene targeting experiments are performed in mice, by deletion of a specific gene in embryonic stem cells using homologous recombination. This approach has been widely used to ‘knockout’ genes encoding cytokine ligands, specific receptors and constituents of signalling pathways. Random gene ablation technology can also be used to discover genes important in reproductive function. Random disruptions to the genome are created by a process known as gene trapping, whereby a reporter gene is inserted into the genome, randomly disrupting genes, or by chemical-based mutagenesis using N-ethyl-N-nitrosourea. The resultant offspring are analysed for interesting phenotypes, and the expression pattern of the disrupted gene can be discovered by tracking reporter gene expression.
Use of cytokine knockout mice to study roles in reproduction
A wealth of information on the roles of cytokines in reproductive biology has been revealed through study of knockout mice (Table I). A useful framework for studying reproductive function in mouse models is provided in Fig. 1. These studies have revealed essential roles for cytokines in regulation of the hypothalamo-pituitary-gonadal (HPG) axis of both male and female mice, as well as production of oocytes from the ovary (Fig. 2). Roles of cytokines in pregnancy, including embryo development, endometrial tissue remodelling and implantation, placental development, protection of the conceptus from external pathogens, and the timing of parturition have also been confirmed and explored using this technology (Fig. 3).
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TGF-β superfamily
Transforming growth factor-β
The three mammalian isoforms of TGF-β (1, 2 and 3) influence a wide variety of biological functions, including cell viability, apoptosis, proliferation, differentiation, adhesion and migration. The three isoforms are encoded by individual genes; however, they share many overlapping functions, and bind the same receptor complex. The synthesis of TGF-β ligand and its receptors appears to be almost ubiquitous in reproductive tissues and consequently TGF-β has many diverse roles in reproductive biology (Ingman and Robertson, 2002
).
Before the application of knockout technology, it was widely believed that the three isoforms were functionally redundant. However, the discovery that knockouts for the different TGF-β isoforms display quite distinct phenotypes clearly showed that each isoform is critical to normal development, and serve different roles. Without TGF-β1, 50% of embryos do not survive past the pre-implantation stage (Kallapur et al., 1999), or have defective yolk sac vasculogenesis and hematopeioesis (Dickson et al., 1995). The embryos which do survive probably do so because of the presence of TGF-β2 and 3, as 100% of mice carrying a dominant negative receptor transgene, whereby none of the TGF-β isoforms can signal transduce, die in utero (Goumans et al., 1999). Mice deficient in TGF-β2 and 3 do not survive longer than 24 h after birth due to defects in cardiovascular development (Sanford et al., 1997), and lung and palate development (Proetzel et al., 1995), respectively.
Approximately half of TGF-β1 knockout mice develop normally in utero, but die from multi-organ inflammatory lesions around the age of weaning (Shull et al., 1992; Kulkarni et al., 1993), preventing analysis of adult reproductive function. This can be overcome by rendering the mice immunocompromized, which prevents inflammatory pathology and increases the lifespan of TGF-β1 knockout mice (Diebold et al., 1995; Letterio et al., 1996; Kobayashi et al., 1999). Using TGF-β1 knockout mice on a severe combined immunodeficiency background, TGF-β1 was shown to be critical for both male and female fertility. Female mice deficient in TGF-β1 have impaired ovarian function, due to dysfunctional LH secretion and a requirement for TGF-β1 in the ovarian follicle, leading to disrupted estrous cycles, reduced number of ovulated oocytes and reduced developmental competence of these oocytes (Ingman et al., 2006). The result of these lesions is greatly reduced fertility, however, some TGF-β1 knockout female mice are able to carry pregnancies to term and deliver overtly normal pups.
Deficiency of TGF-β1 in male mice also causes severe infertility (Ingman and Robertson, 2007). Reduced LH secretion leads to diminished testosterone output by the testes. The null mutation also leads to sexual dysfunction, which appears to be independent of testosterone secretion. Male mice show outward signs of sexual interest in receptive female mice, however are incapable of performing intromission, possibly due to erectile dysfunction. TGF-β has also been shown to be a regulator of prostate epithelial cells, as a dominant negative receptor targeted to the prostate had increased number of cells and reduced apoptosis (Kundu et al., 2000).
Activin
Activins (A, B and AB) are closely related to TGF-βs, and signal through a common pathway (via Smads). Activins act as locally produced paracrine factors in the ovary, uterus, placenta and testis. In females, activins are associated with ovarian biology (Findlay, 1993), placental development and function (Qu and Thomas, 1995; Caniggia et al., 1997) and endometrial decidualization (Jones et al., 2002; Tierney and Giudice, 2004).
Attempts to decipher the exact reproductive roles of activins have been confounded by the existence of multiple highly homologous related subunits, which form closely related dimers. Ablation of activin βA results in neonatal lethality due to major malformation of the jaw, preventing feeding (Matzuk et al., 1995b), whereas mice lacking activin βB subunit survive to adulthood with minor defects, including prolonged gestation and impaired lactation (Vassalli et al., 1994). Double knockouts have additive effects (Matzuk et al., 1995b). The apparent distinct functions for βA and βB have been attributed to differences in spatio-temporal expression or affinity for the common receptors. This was substantiated by the rescue of the neonatal lethality in βA deficient mice by ‘knocking-in’ the βB gene into the βA locus in the knockout mice, such that βB expression is driven by the βA promoter (Brown et al., 2000). These mice survive to early adulthood, but with reproductive abnormalities, including hypogonadism, delayed male onset fertility, defective folliculogenesis and reduced fertility in females. This demonstrates a unique approach in a multigene family where redundancy can be used as an advantage to rescue lethality, enabling investigation of more subtle differences in function of family members. Components of the signalling pathway, cell surface receptors (Alk-4, ActRIIB) and intracellular mediators Smads (2, 3 and 4) have been knocked out—generally resulting in embryonic lethality (reviewed in Ethier and Findlay, 2001; Jones et al., 2006). An exception is the activin type II receptor (ActRII); the null females are viable but infertile due to a block in folliculogenesis and suppressed FSH levels (Matzuk et al., 1995a).
Colony-stimulating factors
Colony-stimulating factor-1
A spontaneously occurring genetic mutation which caused severe osteopetrosis led to the discovery of CSF-1 as a critical cytokine in osteoclast and macrophage development (Wiktor-Jedrzejczak et al., 1990; Yoshida et al., 1990), and in reproductive function in both male and female mice (Pollard, 1997). CSF-1 regulates mononuclear phagocyte and macrophage growth, viability and differentiation, and is a major chemoattractant for these cells (Tushinski et al., 1982; Webb et al., 1996). Studies using these mice have been instrumental in defining critical roles for CSF-1, and CSF-1-regulated macrophages, in reproductive function.
Male mice lacking CSF-1 have severe infertility, caused primarily by defective HPG axis signalling. Levels of LH are low due to defects in the hypothalamus, which leads to low serum testosterone and a cascade of defects including low sperm number and reduced libido (Cohen et al., 1996; Cohen et al., 1997a; Cohen et al., 2002). Targeted disruption of the CSF-1 receptor revealed a similar phenotype (Dai et al., 2002).
Female mice lacking CSF-1 also exhibit defects in the HPG axis as well as other defects that compromise reproductive function. The number of antral follicles and oocytes ovulated in CSF-1 deficient mice is reduced, and CSF-1 deficient mice are unresponsive to exogenous gonadotropins, suggesting that CSF-1 acts locally in the ovary to promote ovulation (Araki et al., 1996; Cohen et al., 1997b). Once established, pregnancy proceeds normally in CSF-1 deficient mice, however, they have impaired innate immune defences when challenged with Listeria infection, revealing a further role for CSF-1 in protection of the conceptus against infection (Guleria and Pollard, 2000).
Granulocyte macrophage-CSF
The survival, proliferation, differentiation and activation of cells of the myeloid leukocyte lineage (i.e. monocytes, macrophages and granulocytes) are regulated by GM-CSF. This cytokine has important functions in establishment of maternal tolerance to fetal-placental tissues, and promotion of early pregnancy events (Robertson, 2007). The ovaries of female GM-CSF knockout mice contain normal numbers of leukocytes however the activation state of these leukocytes is altered, with increased nitric oxide production and reduced expression of class II major histocompatibility complex on ovarian macrophages and dendritic cells (Jasper et al., 2000). The mice have a modest increase in estrous cycle length and normal ovulation rate, however luteinization following ovulation is compromised, with lower progesterone output during early pregnancy, potentially caused by altered leukocyte activation.
Litter size at weaning was found to be reduced in GM-CSF knockout breeding pairs, due to late gestational and peri-natal loss (Robertson et al., 1999). Comparisons between fetal and pup weights between offspring of GM-CSF knockout females mated with GM-CSF knockout or heterozygote males revealed that both maternal and fetal sources of GM-CSF are important for normal fetal development, and that defects are likely to be due to insufficiencies in placental growth (Robertson et al., 1999). This may be due to impaired pre-implantation embryo development, as GM-CSF deficient blastocysts have reduced total cell number, which can be rescued by culturing embryos in the presence of GM-CSF (Robertson et al., 2001).
Leukaemia inhibitory factor
LIF is one of the few genes whose expression is obligatory for embryo implantation. Knockout of LIF results in total female infertility, caused by failure of the blastocyst to attach to the endometrial epithelium (Stewart et al., 1992). In the mouse uterus, LIF is produced by the luminal epithelium and epithelial glands, and is up-regulated from the time of ovulation until implantation (Bhatt et al., 1991). Both luminal epithelium and blastocysts express LIF receptors, suggesting LIF is required for maternal receptivity and/or embryo development (Chen et al., 1999; Ni et al., 2002). Indeed, there is evidence that the epithelial development and gene expression is defective in LIF knockout mice (Sherwin et al., 2004; Fouladi-Nashta et al., 2005). Furthermore, immune cell populations are markedly altered in the peri-implantation phase in LIF knockout mice, suggesting that LIF has roles, directly or indirectly, in regulating leukocyte trafficking or distribution in the uterus (Schofield and Kimber, 2005). Pregnancy can be rescued in the LIF null mouse by LIF injection on the day of implantation and LIF deficient embryos implant successfully in a wild-type recipient female, indicating that maternal, but not embryonic, LIF production is essential in the peri-implantation period (Stewart et al., 1992). However, reduction of LIF expression in 2-cell embryos by microinjection of antisense oligonucleotides, decreases rate of development to the blastocyst stage (Cheng et al., 2004), suggesting that LIF promotes, although is not essential for, pre-implantation embryo development.
Interestingly, a more severe phenotype is observed when the specific LIF receptor is knocked out; null progeny have widespread abnormalities including severely abnormal placentae, and die shortly after birth (Ware et al., 1995). This suggests that the LIF receptor binds additional ligands.
ILs and their receptors
Interleukin-10
Trophoblast invasion of maternal decidua and placental development is a tightly regulated event involving intricate crosstalk between fetal and maternal cells, to promote yet regulate invasion. In vitro studies have implicated roles for a number of cytokines, but verification in vivo has been troublesome. An exception is IL-10, a Th2 cytokine proposed to be a major player in suppressing endometrial inflammatory responses during pregnancy. Although no perturbation of uterine immunological environment was observed in IL-10 knockouts housed in specific pathogen free conditions (White et al., 2004), differences in the structure and function of the placenta were observed (Roberts et al., 2003). Placentae showed a relative expansion of the labyrinth zone, leading to increased efficiency in nutrient transfer to the developing fetus.
However, the primary role of IL-10 in pregnancy appears to be protection of the developing fetus against pathogens. IL-10 knockout mice have a greater susceptibility to some pregnancy pathologies when challenged with an infection. Lipopolysaccaride (LPS) causes fetal resorption (Murphy et al., 2005) and preterm labour (Robertson et al., 2006) when given in low doses to pregnant IL-10 knockout mice during early or late gestation, respectively. No effect on pregnancy was observed when wild-type mice were given the same dose. IL-10 provides this protection via uNK cells and possibly macrophages, through inhibition of inflammatory cytokines including TNF, IFN- and IL-6 (Murphy et al., 2005; Robertson et al., 2007).
Interleukin-11
IL-11 is a cytokine closely related to LIF and is expressed in abundance in the mouse decidua after implantation. As with LIF knock out mice, IL-11 receptor (IL-11R)-null progeny are viable and essentially normal, except female mice are infertile (Robb et al., 1998). In this case, blastocyst implantation occurs and is followed by the primary decidual response in the anti-mesometrial subepithelial stroma. Between days 5 and 6 of pregnancy marked differences are evident between wild-type and knockout implantation sites: although the decidualization response progresses in wild-type mice with the formation of the secondary and mesometrial decidual zone, decidualization is stalled in the IL-11R knockout. Secondary decidual formation is dramatically retarded, eventually leading to overgrowth of embryonic trophoblast tissues and implantation failure. A number of genes encoding extracellular matrix components are differentially expressed between wild-type and IL-11 knockout mice early in the decidualization response, suggesting that primary decidualization is defective (White et al., 2004).
Interleukin-15
Uterine NK cells constitute a major component of the decidua in both humans and mice. A number of decidual-derived chemokines [macrophage inflammatory protein-1β (MIP-1β), secondary lymphoid chemokine (SLC), monocyte chemoattractant protein-3 (MCP-3)] (Jones et al., 2004) are able to stimulate migration of human uNK cell precursors in vitro (Campbell et al., 2001), although knockout of murine homologues fails to identify any requirement for a single chemokine for their endometrial recruitment (Chantakru et al., 2002). In contrast, knockout of the cytokine IL-15, a cytokine critical for lymphoid NK cell differentiation, demonstrates an essential role in uNK cell differentiation (Ashkar et al., 2003). In its absence, uNK cells are completely ablated from implantation sites, and decidual integrity and vascular development are compromised. Transplantation studies verified that autocrine production of IL-15 is not required, and that peripheral NK cells require a uterine signal. However, despite their abundance and apparent roles in decidual formation, absence of NK cells does not adversely affect pregnancy in mice, although a small but significant reduction in birthweight was observed, suggesting a suboptimal uterine environment (Barber and Pollard, 2003). The only other cytokine definitively shown to be critical in recruitment of immune cells to the endometrium is eotaxin; eosinophils are absent from the uterus in the eotaxin knockout mouse, but again no uterine functional deficiency was found (Gouon-Evans and Pollard, 2001).
Multiple IL ligand knockouts
In addition to IL-10, a number of other Th2 cytokines have been selectively mutated to explore the role for Th2 cytokines at the maternal–fetal interface. Individually these knockouts have no reproductive phenotype, potentially due to a high degree of compensatory pathways that protect fertility. To verify this, quadruple knockouts of Th2 cytokine genes were generated, through intercrossing of double, then triple knockout F2 mice (Fallon et al., 2002). Despite lacking IL-4, IL-5, IL-9 and IL-13 genes and having compromised Th2 responses as determined through parasitic challenge, female mice reproduced successfully. Litter sizes were not affected when female quadruple knockouts were crossed with either males of the same background strain (known as a syngeneic mating) or of a different background strain (known as an allogeneic mating). This suggests that allogeneic pregnancy is not dependent on a maternal Th2 bias. However, there may be more subtle effects which are dependent on the specific allogeneic cross. An IL-5 only knockout on a C57/Bl6 background had a 9% reduction in placenta weight in late pregnancy when mated with a wild-type CBA male, but no reduction when mated with a C57/BL6 or BalbC male (Robertson et al., 2000).
Additionally, the quadruple knockout females are likely to be unable to respond appropriately to an immunological or inflammatory challenge during pregnancy, which may lead to increased fetal loss or preterm labour as observed in IL-10 knockout mice (Murphy et al., 2005; Robertson et al., 2006).
IL receptors
Despite its abundance in reproductive tract tissues, no deficiency in fertility was observed with genetic knockout of the IL-1 receptor (type I) in male (Cohen and Pollard, 1998) or female mice (Abbondanzo et al., 1996), apart from slightly reduced litter sizes in female IL-1R knockout mice. This is in contrast to the drastically reduced implantation rate when IL-1 biological activity was blocked by administration of IL-1 receptor antagonist in the peri-implantation period (Simon et al., 1994). The absence of a placental phenotype is undoubtedly related to redundancy in this system, as many other cytokines and growth factors could compensate for lack of IL-1 in stimulating trophoblast migration (e.g. activin, IL-6, IL-15) (Caniggia et al., 1997; Zygmunt et al., 1998; Meisser et al., 1999).
The problem of redundancy among family members can be overcome by targeting a common receptor. The IL-2 receptor chain is shared amongst IL-2, -4, -7, -9 and -15. Ovarian cycle regularity is affected in mutants lacking IL-2R (Miyazaki et al., 2002), however, they are fertile and no abnormalities were noted throughout pregnancy, with the exception of an absence of uNK cells and associated decidual phenotype, later verified to be due to lack of IL-15 action.
Tumour necrosis factor-
Similar discrepancies in phenotype to IL-1 and its receptor exist between knockouts of TNF- ligand and its receptor. Although no reproductive abnormalities were reported in the absence of the ligand (Taniguchi et al., 1997), detailed analyses of reproductive performance in female TNF-RI null mice identified disruption of the estrus cycle, leading to premature fertility loss, and increased sensitivity of the prepubertal ovary to gonadotropin stimuli (Roby et al., 1999). These effects were not seen in TNF-RII null females, thus demonstrating divergent roles for the receptor isoforms in ovarian function and steroidogenesis.
Manipulation of negative regulators of cytokine action
In addition to gene ablation of ligand, receptor or signalling components, cytokine action can be explored by knockout or overexpression of genes encoding negative regulators. This is a useful approach for the initial understanding of a gene family involvement in a process, bypassing redundancy issues. Suppressors of cytokine signalling (SOCS) are a family of negative regulators of cytokine signalling. Their expression is acutely stimulated at the transcription level by ligand-induced activation of the cytokine pathways, producing a self-regulated fine-tuning mechanism for cytokine action. There are eight SOCS family members, each differing in terms of cytokine pathway specificity, and functioning in a variety of ways, e.g. through targeting of Janus Kinase (JAK) proteins for degradation (Alexander, 2002; Larsen and Ropke, 2002). SOCS3 is up-regulated in response to IL-11, LIF and IL-6, amongst others factors. SOCS3 null homozyogotes die in midgestation (E11.5–12.5), due to defective placental formation resulting in increased numbers of invasive giant trophoblast cells and reduced spongiotrophoblast (Takahashi et al., 2003). As LIF promotes the differentiation of trophoblast giant cells, a double knockout of LIFR and SOCS3 was created, and this rescued the SOCS3 null phenotype (Takahashi et al., 2003). Thus suppression of LIF signalling is clearly fundamental for normal placental development. However, many cytokines and growth factors, including IL-10 which is known to be important for placental development, are also regulated by SOCS3, and thus may be involved.
Cytokine action can also be inhibited by the overexpression of endogenous binding proteins or negative regulators. Lefty is a member of the TGF-β superfamily, and can bind to TGF-β type II receptors and inhibit the action of TGF-β (and possibly other ligands) (Ulloa and Tabibzade, 2001). Lefty A was overexpressed locally in the mouse uterus by retroviral transfection (Tang et al., 2005), resulting in implantation failure. Similarly, follistatin, a negative binding protein for activin, has been transgenically overexpressed (Guo et al., 1998), creating a functional activin knockout. This results in reproductive abnormalities, including decreased testis size and defective Leydig cell function and spermatogenesis in males, while females have small ovaries and become infertile with advancing age. The neonatal lethality of the follistatin knockout (Matzuk et al., 1995c) was overcome by a conditional knockout to examine ovarian phenotype (Jorgez et al., 2004). The granulosa cell specific promoter Amhr2 driving cre recombinase expression was used to locally inactivate the follistatin gene, disrupting fertility through reducing numbers of ovarian follicles, fertilization defects and elevated gonadotropins, eventually leading to infertility. This phenotype is strikingly similar to symptoms of premature ovarian failure, supporting a role for tightly regulated activin bioactivity in maintaining normal ovarian function. A somewhat different phenotype was seen when activin action was enhanced by knockout of the inhibin subunit (Draper et al., 1998), thus removing the competitive antagonism of activin action. Mice lacking inhibin were normal at birth, but both males and females developed severe gonadal tumours (reviewed in Chang et al., 2001).
Caveats associated with the use of knockout technology
Despite the large amount of knowledge that can be gained by knockout studies, there are some important considerations to be taken when investigating the role of cytokines in reproductive biology using this approach.
Redundancy
Depletion of a single cytokine may not have any noticeable effect, despite other evidence suggesting it to have an important role in the reproductive process. As most cytokines work together to create a cytokine milieu that will overall influence how a cell will grow and differentiate, the loss of one cytokine can, in some circumstances, be made up for by altered production of others. This problem can be overcome to some extent by the use of multiple knockouts. In situations where multiple ligands bind the same receptor, a dominant negative receptor approach can knockout the effects of all ligands at once.
Lethality
Cytokines play many roles during the life of an organism, during development, in haematopoiesis, in the maintenance of homeostasis and health, and the initiation of cell death or differentiation. Whole organism knockout of a particular cytokine can have dramatic consequences on specific organ development, to the extent that the organism does not function, in which case we see a lethality phenotype. Lethality phenotypes severely compromise the ability to analyse reproductive function. However, some analysis can still be achieved by transplanting the organ of interest into a healthy wild-type host.
Delineating systemic versus local effects
Another potential problem is developmental defects that cause secondary effects on reproductive function. The reproductive system is particularly susceptible to secondary effects of cytokine depletion because of its large dependence on sex hormone production. Hormone levels are regulated at the level of the hypothalamus, pituitary and gonads by positive and negative feedback mechanisms, and can be influenced by a large array of other endocrine factors including leptin, cortisol and thyroid hormone. Therefore, altered function in a wide variety of organs can lead to imbalances in sex hormones leading to infertility. Therefore, when a fertility phenotype is observed in a knockout animal, the question must be asked: is it caused by a primary effect on the reproductive organ of interest, or as a secondary consequence of altered functioning of another tissue? The general approach to this question in the past has been to analyse sex hormone production and ovarian cyclicity, and conduct organ transplant studies or hormone replacement studies.
Subtle effects
As we begin to understand more about the importance of fetal growth for adult health, subtle effects on fetal development take on greater significance. Even small changes in nutrient delivery to the fetus can program post-natal and adult metabolic status and lead to increased susceptibility to a range of adult onset disease, including stroke, hypertension and non-insulin dependent diabetes (reviewed by McMillen and Robinson, 2005; Barker, 2006). Although a particular cytokine may not be necessary for pregnancy to proceed or for normal litter sizes, it is important to consider more subtle effects on fetal and placental development, and growth of the neonate, to understand the full impact of gene ablation on reproductive physiology.
Specific pathogen free conditions
Laboratory mice in research institutions are generally housed in a specific pathogen free environment, and are therefore not challenged with the array of pathogens most mice and humans are exposed to. Disrupting cytokine networks may lead to reduced capacity to respond to these challenges, which would not be observed under normal laboratory conditions.
Strategies to improve the use of gene knockout technology
A number of alternative strategies can be used in place of, or to complement, conventional gene knockout that will overcome problems of embryonic lethality, complications through actions in other organs, and developmental defects caused by the long-term absence of a gene.
Regulatable gene ablation
Ablation of a gene can be spatially or temporally regulated, so that only the organ of interest is affected, or the mutation is induced only at a particular stage of development. A useful method is the cre/lox system, whereby 2 loxP sites are inserted into the gene, flanking a critical section (Gu et al., 1994). Gene expression occurs normally unless the cre recombinase protein is co-expressed, as cre inverts the genetic material between the two sites back to front, effectively disabling the gene. Cre expression is then controlled by a transgene, whereby expression is limited by a cell lineage specific promoter, or is inducible, e.g. by using a promoter regulated by tetracycline or RU486. Alternatively, a dominant negative receptor approach can be used, whereby the dominant negative receptor is regulated by a cell lineage specific or inducible promoter. The use of conditional knockouts in reproductive biology research is limited by the availability of cell or tissue specific promoters. Lack of a tissue-specific promotor can be overcome by using adenovirus expressing cre-recombinase (Baba et al., 2005) and targeted delivery (e.g. injection into the mouse uterine lumen; Beauparlant et al., 2004).
Temporary gene ablation: gene knock downs
Genes can be transiently down-regulated or ‘knocked down’ by targeted blockade of gene expression, either systemically or within a specific tissue. Transient knockout approaches offer a more rapid and more economical method to examine the specific actions of a gene product at a particular time point.
One approach is to use antisense technology, the efficacy of which has been improved dramatically by the development of morpholino antisense oligonucletides (Summerton and Weller, 1997). These are short (around 25 bp) modified DNA sequences complementary to the mRNA of the gene of interest, designed to span the 5'UTR and the beginning of the coding sequence. Binding of the antisense prevents translation initiation by blocking ribosomal interaction with the ATG start codon. Alternatively, morpholino oligonucleotides can target splice junctions and modify pre-RNA, resulting in abnormal protein synthesis. Introduction of the oligonucleotides into cells is achieved through microinjection, cell scraping or by specialized delivery reagents such as EPEI (ethoxylated polyethylenimine) or Endo-porter, that aid endocytotic uptake (Morcos, 2001). Temporary knockdown of genes has been widely achieved by microinjection into embryos, and recently in cell culture systems (Heasman, 2002).
An alternative, more recently developed technology for gene knockdown involves the use of short interfering RNA (siRNA) (reviewed by Hannon, 2002). This approach exploits evolutionarily conserved cellular mechanisms to protect against parasitic and pathogenic nucleic acids. Small lengths (19–22 bp) of double stranded RNA designed against the gene of interest are introduced to the cell where they interact with intracellular machinery to form RNA-induced silencing complexes (RISCs). These unwind the siRNA strands, enabling specific binding to the complementary mRNA sequence, followed by cleavage and destruction of the now doubled stranded mRNA, thus preventing subsequent translation.
How will cytokine knockout mice improve reproductive medicine?
Gene ablation studies in mice can provide clues about the role of cytokines in human reproduction. Some genes associated with human reproduction have been identified using screening methods such as gene arrays, to be differentially expressed between fertile and infertile individuals or populations. However, the absolute requirement of a particular gene for fertility is virtually impossible to verify in humans, and enormous heterogeneity between individuals and the multifactorial nature of infertility add further complexity. Thus application of findings from gene ablation studies in mice can be invaluable in shedding light upon reproductive processes in humans, in combination with comparison of expression patterns in human tissues and in vitro functional studies.
Improving in vitro fertilization
Maternal-derived GM-CSF was shown by mouse knockout studies to improve pre-implantation embryo development, fetal and placental growth, and pup weight and survival (Robertson et al., 1999, 2001). During in vitro fertilization and culture for infertile couples, this cytokine is absent from traditional culture media. Culturing normal mouse embryos in the presence of exogenous GM-CSF has been found to improve fetal and post-natal growth, with growth trajectories closer to in vivo developed offspring compared with embryos cultured in vitro in the absence of GM-CSF (Sjoblom et al., 2005). Importantly, human cultured embryos also benefit from exogenous GM-CSF, with improved development to blastocyst stage, increased hatching, and increased inner cell mass due to reduced apoptosis (Sjoblom et al., 1999, 2002). This cytokine may become a routine additive to in vitro fertilization culture protocols in the future.
Improving oocyte development
Successful pregnancy following IVF positively correlates with intrafollicular content of TGF-β1 at the time of oocyte retrieval (Fried and Wramsby, 1998). In the complete absence of TGF-β1, infertility was found to be caused by oocyte incompetence leading to early embryo arrest in knockout mice (Ingman et al., 2006). This suggests that some human infertility or subfertility may result from impaired oocyte development secondary to low levels of ovarian TGF-β1. We can now investigate interventions to increase intrafollicular levels of TGF-β1 using this mouse model, including dietary supplementation, as orally delivered TGF-β1 is known to cross the gastro-intestinal wall and rescue the TGF-β1 knockout mouse autoimmunity phenotype (Letterio et al., 1994).
Improving implantation
Similarities between mice and humans in the early stages of embryo implantation have made knockout mouse models useful in identifying those genes which may be important for the establishment of human pregnancy. As described earlier, gene ablation of LIF results in a failure of embryo implantation (Stewart et al., 1992). LIF is therefore an exciting candidate for either enhancing or preventing pregnancy in humans. In humans, LIF is expressed by surface and glandular epithelium, and is elevated at the time of implantation as it is in the mouse (Bhatt et al., 1991; Charnock-Jones et al., 1994). LIF is detectable in uterine fluid, and there is evidence that reduced levels are present in women experiencing unexplained infertility (Laird et al., 1997), correlating to lower levels of expression by endometrial cells (Tsai et al., 2000; Dimitriadis et al., 2006). However, low LIF levels in uterine fluid were found to be predictive of implantation success following IVF (Ledee-Bataille et al., 2002), indicating a delicate balance is required for optimal embryonic/uterine stimulation. The clinical application of these findings is being explored. Measurement of LIF in uterine flushing is currently being investigated as a potential tool for diagnosis of infertility (Mikolajczyk et al., 2003). Furthermore, mutations in the LIF gene have been identified in women with unexplained infertility and spontaneous abortion (Giess et al., 1999; Steck et al., 2004; Kralickova et al., 2006).
LIF treatment increases rate of fertilization of sheep oocytes, and enhances embryo quality during pre-implantation embryo culture in sheep, mice and humans (Cheung et al., 2003; Ptak et al., 2006). A preliminary study demonstrated improved murine implantation, pregnancy and viability rates when LIF was administered during transcervical blastocyst transfer, whereas a neutralizing antibody exerted negative effects on implantation rates (Mitchell et al., 2002). Similar experiments in rhesus monkeys prevented pregnancy, strongly supporting the potential for translation to human biology (Sengupta et al., 2006). However, human implantation is likely to be more complex, with additional layers of redundancy evolved to protect fertility. Closely related IL-11 is limited to a role in decidualization in the mouse, but broader actions are indicated in the human endometrium, where it shares an identical spatial and temporal expression pattern with LIF in the peri-implantation phase (Dimitriadis et al., 2000). This hints at a possible redundancy between the ligands in the human endometrium, which may necessitate the targeting of multiple cytokines for contraceptive development.
A mouse model of menstruation
Menstruation and the associated endometrial repair is a challenging problem to study, as it occurs in a very small number of species, not including mice. For this reason, a mouse model mimicking menstruation has been developed (Finn and Pope, 1984; Brasted et al., 2003), where the endometrium is artificially decidualized, prior to progesterone withdrawal to trigger the onset of endometrial breakdown and subsequent repair. This simulates menstruation in the human and there are broad similarities in the patterns of inflammatory leukocyte influx, production and activation of matrix metalloproteinases (MMPs) and rapid regeneration and repair (Kaitu’u et al., 2005). Importantly endometrial breakdown and repair is retarded by treatment with antibodies that effectively knock out neutrophils (Kaitu’u-Lino et al., 2007), confirming that the neutrophil infiltrate observed in the premenstrual phase in human endometrium is involved in the initiation of menstruation. This model can now be applied to knockout mice, to test the involvement of individual cytokines in the inflammatory breakdown and post-menstrual repair, information that will assist in the future development of treatments for abnormal menstrual bleeding.
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Both the male and female reproductive tracts undergo extensive development and remodelling over the course of an individual’s life. Cytokines and cells of the immune system are intimately involved in many of the processes critical to production of male and female gametes, in the endometrium during menstruation and implantation, during placental and embryonic growth, and during parturition. Knockout mouse models have greatly assisted in revealing non-redundant essential roles that particular cytokines serve. Sophisticated new approaches, including regulatable and transient gene silencing, are now being utilized to further explore the role of cytokines in particular reproductive processes. These technologies are expected to challenge, support and provide novel concepts on the fundamental roles of cytokines in reproduction in mice, and will form the basis of translational research into a better understanding of reproductive processes and pathologies in humans.
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TOPAbstractIntroductionMaterials and MethodsConclusionAcknowledgementsReferences |
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The authors thank A/Prof Sarah Robertson (University of Adelaide, SA, Australia) for critical review of the manuscript and Sue Panckridge (Prince Henry’s Institute for Medical Research, Vic, Australia) for assistance in creating figures. This review aims to discuss how knockout technology has provided insight on the role of cytokines in reproductive biology. The authors acknowledge that many important papers on the roles of cytokines in reproductive biology discovered by other means have been omitted from this review due to space restrictions. For more general information on cytokines in specific reproductive tissues or processes, excellent reviews are identified in the reference list by an asterisk.
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