Tribbles (TRIB) proteins, a family of evolutionary conserved psuedokinase proteins, modulate various signalling pathways within the cell. The regulatory roles of TRIB make them an important part of a number of biological processes ranging from cell proliferation to metabolism, immunity, inflammation and carcinogenesis. Innate immune system plays a pivotal role during the regulation of reproductive processes that allows successful creation of an offspring. Its involvement initiates from fertilization of the oocyte by spermatozoon and lasts throughout early embryonic development, pregnancy and labour. Therefore, there is a close cooperation between the reproductive system and the innate immune system. Evidence from our lab has demonstrated that improper activation of the innate immune system can reduce embryo implantation, thus leading to infertility. Therefore, control mechanisms regulating the innate immune system function can be critical for successful reproductive events.

Introduction

Tribbles (TRIB), first identified in Drosophila, have gained their names from a fluffy creature in Star Trek Sci-Fi television series. Mutation in the tribbles genes gives the fruit fly a look reminiscent to the fictitious creatures in this series. A rapidly growing body of literature highlights the involvement of TRIB proteins in different physiological and pathological processes ranging from cancer to immune system regulation [1,2]. In recent years, we have gathered evidence that TRIB proteins may have an effect on reproductive processes, too [Basatvat Shaghayegh, Carter Deborah Angela Louise, Kiss-Toth Endre and Fazeli Alireza, unpublished work]. However, understanding of the involvement of TRIB in different reproductive processes is currently scarce and an under investigated area of reproductive biology. Here, in this short review, we will at first discuss potential different functions mediated by different TRIB proteins, present a summary of different reproductive processes and cite the relevant literature investigating TRIB function in these processes or hypothesize the potential involvement of TRIB in reproductive functions. Since TRIB seems to have a major function as regulators of innate immune system, we will particularly highlight the reproductive processes that involve innate immune responses and can be potentially mediated or influenced by TRIB.

Structure and function of tribbles proteins family

Members of TRIB family are encoding evolutionarily conserved psuedokinase proteins. These proteins are involved in modulation of cell functions by regulating intracellular signalling pathways [2]. All TRIB proteins have a central serine/threonine kinase-like domain but they seem to lack robust enzymatic activity. Therefore they may be unable to effectively phosphorylate their target proteins [3]. Hence, it is believed that TRIB may be working with a wide range of targets as scaffold proteins and controlling various signalling pathways [1]. Scaffold/adaptor proteins smooth the flow of signals by helping with translocation and facilitate proximity of different components of a signalling cascade. They facilitate signal transduction, as for the optimal output of signalling network, there should be a balance between the concentrations of scaffold proteins and their targets [4]. The psuedokinase domain of TRIB protein plays an essential role in the protein-protein interactions with their targets.

TRIB proteins are believed to regulate various events within the cell such as proliferation, metabolism, carcinogenesis, inflammation, cell differentiation, apoptosis and managing cellular stress [5,6]. All three members of the TRIB family, Trib1, Trib2 and Trib3 have been reported as regulators of the innate immune system by interacting with toll-like receptor (TLR)-mediated nuclear factor kappa-B (NF-KB) signalling pathways [79]. NF-KB is a group of key transcription factors that control the expression of various cytokines, chemokines, growth factors and adhesion molecules linked to innate immunity and different inflammatory processes [10].

Trib3 is a negative regulator of TLR2 response to Helicobacter pylori lipopolysaccharide (LPS) in human epithelial cells via the inhibition of NF-KB signal transduction leading to reduced IL-8 expression [7]. Trib3 in this regard is considered as a modulator of inflammatory processes. Indeed, Trib3 was identified as a regulator of the NF-KB signalling pathway earlier by another group. They have discovered that SINK/Trib3 is negatively modulating NF-KB function by inhibiting p65/RelA phosphorylation. As a result transcriptional activity of NF-KB but not its nuclear translocation would be disrupted [11].

Another member of the TRIB family, Trib2 has also been shown to negatively regulate TLR5 ligand-stimulated NF-KB signalling pathway [8]. Wei et al. have demonstrated that Trib2 can act as an anti-inflammatory factor and can affect both effector arms of TLR5 signalling; mitogen-activated protein kinase (MAPK) pathway and NF-KB pathways in opposite ways [8]. The knockdown of Trib2 reduced the phosphorylation of C-jun N-terminal kinase (JNK) and P38 mitogen-activated kinase (P38) but did not affect the phosphorylation of extracellular signal-regulated kinase (ERK). On the other hand, the siTrib2 treatment of the same cell type increased the NF-KB luciferase activity in response to flagellin.

In conclusion, TRIB family proteins seem to have diverse roles in different cell properties ranging from cytoskeletal scaffolding functions to mediating innate immune-response. The rest of this review paper will focus on describing briefly different reproductive processes leading to production of an offspring and will highlight the literature reporting involvement of TRIB family in these processes.

Brief overview of different reproductive processes and events

In mammals, reproductive processes leading to the creation of an offspring involve production of gametes (spermatozoa and oocyte), transfer of the spermatozoa into the female reproductive tract (FRT), sperm and egg transport to the site of fertilization in FRT, conception, embryo development, implantation, pregnancy and the birth of the offspring.

Spermatozoa are produced during a process termed spermatogenesis. During coitus/mating spermatozoa are deposited in FRT and transported to the site of fertilization [12]. The female gamete (oocyte) is generated within the ovaries through a process named oogenesis. Ovaries have another crucial task which is the production of sex hormones essential for the proper function of female reproductive organs. Ovulation is the last stage of oogenesis and is associated with the release of the oocyte into fallopian tubes [13,14].

Maternal interactions with gametes [15] are described as the signals swapped either between the mother and spermatozoa following mating or between the mother and oocyte immediately after ovulation [16]. Interestingly spermatozoa and oocyte alter the proteomic profile of oviductal cell in dissimilar and definite way [17,18]. In other words, the oviductal cells are able to distinguish between spermatozoa and oocyte that helps to provide the appropriate microenvironment for sperm transportation, sperm storage and capacitation, fertilization and early embryo development [1922].

Fertilization is defined as the fusion of oocyte and a spermatozoon which in mammals is taking place in fallopian tube/oviduct. During fertilization, spermatozoa bind to the zona pellucida and go through acrosome reaction, which facilitates penetration of the zona pellucida. Finally the sperm and egg content combine and form the zygote [23]. Upon syngamy, the zygote starts cleavage to ultimately form the blastocyst. The blastocyst moves towards the uterine cavity and hatches from zona pellucida to gain the implantation fitness [24]. Implantation of the embryo is an essential part of a successful pregnancy. It depends on three factors; receptive endometrium, healthy embryo at blastocyst stage and the effective communication between them.

Endometrial receptivity is a time limited process, the endometrium is only ready for the embryo to implant during a specific period of time, named window of implantation (WOI). In human WOI is during the mid-secretory phase of menstrual cycle between days 19 and 23. During this time, the endometrial cells undergo fundamental molecular and morphological changes. The molecular adaptations in endometrial cells that make them receptive for embryo implantation are a result of alterations in the expression of different cytokines, chemokines, growth factors and adhesion molecules with the aim of acquiring the adhesion ligands and losing the inhibitory factors [25,26]. The floating blastocyst commences the communication with the receptive endometrium through growth factors and local hormones in order to implant and establish pregnancy followed by apposition, adhesion and invasion [27].

Maintenance of the pregnancy and the growth and development of the conceptus is hugely dependent on the maternal recognition of the pregnancy. This process requires progesterone and placental hormones. The embryo needs to hint its presence to the mother in order to increase the existence of corpus luteum and as a result, the production of progesterone. Secretion of progesterone regulates the uterine endometrial functions, supports the early embryonic development and placentation [28].

Importance/regulation of innate immune system in males and females

Innate immune system in FRT protects the maternal tract against invading pathogens on one hand and support the growth and survival of the fetus on the other hand [29]. Generally, the innate immune system with the help of its well-known receptors, TLRs, have the ability to rapidly recognize non-self-entities like bacterial and viral particles and further activate the adaptive immunity. Following stimulation by their specific ligands, TLRs induce intracellular signalling pathways leading to the activation of various transcription factors and expression of cytokines, chemokines and anti-microbial factors [30]. It has been reported that presence of an infection in maternal tract is significantly related to pregnancy disorders and infertility [31]. Hence, in normal pregnancy, the maternal innate immune system has a significant role in establishment of the mother–embryo communication as immune cells are abundantly present at the implantation site [32]. The active role of the innate immune system at the site of embryo implantation and its contribution in setting up the interaction between the maternal endometrium and the implanting blastocyst is portrayed in Figure 1. Indeed, the crucial part that the innate immune system is playing in FRT starts earlier and upon deposition of semen into the maternal tract. Insemination stimulates series of immunological and inflammatory reactions that determine the outcome of successful pregnancy. Since spermatozoa are non-self-entities, it is logical to expect spermatozoa to elicit an immune reaction in FRT. However the innate immune process is truly in favour of the pregnancy. For instance, the cytokine expression in response to semen in FRT works as a mediator in facilitating the ovulation process [33].

The Role of immune system at the implantation site

Figure 1
The Role of immune system at the implantation site

Embryo implantation is a unique and tightly regulated event. Maternal immune system plays a significant role in embryo implantation. Secretion of various cytokines, chemokines and adhesion molecules are essential in establishment of the interaction between embryo and endometrial cells. Implantation in human is a three-stage process: (A) Apposition; unstable attachment of blastocyst to the uterine epithelial cells followed by (B) attachment; stable attachment of blastocyst to the uterine epithelial cells and shortly after is (C) invasion; the blastocyst breaches into the epithelial cells of the uterus and is embedded to the decidualized stromal tissue. The accumulations of immune cells i.e., natural killer (NK) cells and macrophages are essential to facilitate embryo invasion. Secretion of IL-8 and angiogenic factors by NK cells regulate embryo invasion. The embryo can only get implanted when endometrium is at receptive statues. Shortening of microvilli and appearance of pinopodes on the surface of endometrial cells and the decidualization of stromal cells are some examples of morphological changes of a receptive endometrium.

Figure 1
The Role of immune system at the implantation site

Embryo implantation is a unique and tightly regulated event. Maternal immune system plays a significant role in embryo implantation. Secretion of various cytokines, chemokines and adhesion molecules are essential in establishment of the interaction between embryo and endometrial cells. Implantation in human is a three-stage process: (A) Apposition; unstable attachment of blastocyst to the uterine epithelial cells followed by (B) attachment; stable attachment of blastocyst to the uterine epithelial cells and shortly after is (C) invasion; the blastocyst breaches into the epithelial cells of the uterus and is embedded to the decidualized stromal tissue. The accumulations of immune cells i.e., natural killer (NK) cells and macrophages are essential to facilitate embryo invasion. Secretion of IL-8 and angiogenic factors by NK cells regulate embryo invasion. The embryo can only get implanted when endometrium is at receptive statues. Shortening of microvilli and appearance of pinopodes on the surface of endometrial cells and the decidualization of stromal cells are some examples of morphological changes of a receptive endometrium.

It is well documented that sex hormones (oestradiol and progesterone) can affect both the function and expression of the TLRs in FRT and the expression of nearly all TLRs are at their peak during the secretory phase of female menstrual cycle which is associated with lower levels of oestradiol presence in FRT compared with the proliferative phase [29]. Oestradiol can reduce the inflammatory response of pathogens by inhibiting NF-KB function and limit the transcription of proinflammatory cytokines such as macrophage inhibitory factor (MIF) and IL-6 and chemokines like IL-8. Oestradiol blocks the nuclear translocation of NF-KB or suppresses the degradation of its cytoplasmic inhibitors [34,35].

The expression and function of TLRs have been investigated in epithelial cells of female [36] and male [37] reproductive tract. Results from both in vivo [38] and in vitro experiments [39,40] showed that stimulation of endometrial TLRs with their specific agonists, have decreased the binding of embryo to the maternal endometrial cells. In the above mentioned studies, the activation of TLRs with their ligand at the time of implantation, significantly affects the endometrial receptivity which hugely decreases the rate of successful embryo implantation. Treatment of murine uterine horn with TLR2/6 ligand (FSL-1, a synthetic diasylated lipoprotein) has altered the tissue structure which affects the receptivity of the endometrial cells to embryo [38]. Stimulation of TLR3 in endometrial cell-line, RL95-2 with its ligand poly I:C (synthetic double-stranded RNA) has reduced actin polymerization and CD98 expression. These modifications in response to TLR3 activation hugely disturb the endometrial receptivity and reduce the number of attached embryos to the endometrial cells [39]. CD98 expression has been reported as an important molecule, up-regulated at the implantation site in endometrial cells and is mandatory for blastocyst binding to the endometrium [41].

Similar to their female counterparts, presence of bacterial, viral or yeast infection in male reproductive organs is also associated with inflammatory environment that is contributed to impaired sperm production and sperm maturation that consequently leads to infertility [42]. It has also been reported that testosterone, the sex hormone produced in male reproductive tract, has an inhibitory effect on TLR expression namely TLR4 in testis. Testosterone seems to have immunosuppressive control role by affecting the balance between anti- and pro-inflammatory cytokine expressions in non-immune cells such as sertoli cells [43].

Potential involvement of tribbles in infertility

Although substantial research has been performed on TRIB function in different biological process [2,3,5], to the best of our knowledge, only one study reported on the involvement of TRIB proteins in mammalian reproduction. Brisard et al. [44] have investigated the expression pattern of all three members of TRIB protein family during oocyte maturation. They have confirmed the expression of these proteins in cumulus cells (CC) surrounding mouse and bovine oocyte with Trib2 showing the highest and Trib3 the lowest level of expression in CC of both species. Their experiments showed a remarkable reduction in Trib2 expression during oocyte maturation whereas Trib1 and Trib3 expression was significantly increased during this process. Differences in the expression patterns of different TRIB proteins during oocyte maturation could be explained by the different roles TRIB may have in different biological processes. Trib2 is involved in cell proliferation and that is explained by its over expression in different cancers and its down-regulation in oocyte maturation process [44].

Considering the fundamental function of innate immunity in both the female and male reproductive system and the previous studies on the regulatory role of TLRs signalling pathway by TRIB proteins, we speculate that TRIB may have significant modulatory roles in both the male and female reproductive system. Their regulation could cover a range of events within FRT such as implantation and establishment of pregnancy. Hence, it is plausible to suggest that TRIB may be involved in processes such as sperm transport and embryo implantation, as both these processes have potential to trigger the innate immune system in FRT. In male reproductive system they could affect the production and maturation of spermatozoa.

The diagram in Figure 2 shows the possible regulatory interactions TRIB protein may have in TLRs signalling pathway as a well-known family of innate immune system.

The potential involvement of Tribbles proteins in TLR-induced NF-KB and MAPK pathways

Figure 2
The potential involvement of Tribbles proteins in TLR-induced NF-KB and MAPK pathways

The potential involvement of TRIB proteins in the TLRs signalling pathway is depicted with thick red arrows. TLRs initiate their intracellular signalling pathway upon stimulation by their specific ligand. Almost all TLRs (except for TLR3) are signalling via myeloid differentiation primary response gene-88 (MyD-88) adaptor protein. So TLRs signalling pathway is either MyD-88-dependent or MyD-88-independent. MyD-88-dependent pathway ended up in the activation of two separate transcription factors: NF-κB and activator protein-1 (AP-1). TNFR-associated factor 6 (TRAF6) and IL-1R kinases (IRAKs) are actively involved in TLR signalling pathways. Upon activation, TRAF6 phosphorylates and degrades NK-κB inhibitors (IKB) that helps with NF-κB translocation into the nucleus. It also phosphorylates members of MAPKs pathway and activate AP-1 transcription factor. To regulate TLRs signalling pathway TRIB proteins have been reported to be interacting with NF-κB subunits and members of MAPK pathway at two different levels depicted by arrows in the schematic diagram.

Figure 2
The potential involvement of Tribbles proteins in TLR-induced NF-KB and MAPK pathways

The potential involvement of TRIB proteins in the TLRs signalling pathway is depicted with thick red arrows. TLRs initiate their intracellular signalling pathway upon stimulation by their specific ligand. Almost all TLRs (except for TLR3) are signalling via myeloid differentiation primary response gene-88 (MyD-88) adaptor protein. So TLRs signalling pathway is either MyD-88-dependent or MyD-88-independent. MyD-88-dependent pathway ended up in the activation of two separate transcription factors: NF-κB and activator protein-1 (AP-1). TNFR-associated factor 6 (TRAF6) and IL-1R kinases (IRAKs) are actively involved in TLR signalling pathways. Upon activation, TRAF6 phosphorylates and degrades NK-κB inhibitors (IKB) that helps with NF-κB translocation into the nucleus. It also phosphorylates members of MAPKs pathway and activate AP-1 transcription factor. To regulate TLRs signalling pathway TRIB proteins have been reported to be interacting with NF-κB subunits and members of MAPK pathway at two different levels depicted by arrows in the schematic diagram.

Conclusion

TRIB proteins expression and function are cell-type specific. They are involved in various cell functions and act as regulators of different signalling pathways, MAPK and NF-KB signal transduction for instance [3,45,46]. TRIB expression is modulated by different stimuli [47,48] as an example, TRIB-2 expression can be stimulated in response to TLR ligands [8]. Consequently any alteration in the expression of TRIB can affect their function and the signalling pathway which they control. As explained earlier both male and female reproductive tracts are exposed to entities that can stimulate the innate immune system and lead to the transcriptional activation of downstream genes. Unnecessary activation of the immune system impairs the balanced milieu within the reproductive tract and affects the fertility outcome. This demands a control system to guarantee the successful reproduction which is where the TRIB protein can greatly participate.

Authors acknowledge the support of the European Cost Action, Epiconcept (FA1201) towards this investigation.

Funding

This investigation was partially funded by an Epiconcept European Cost Action (FA1201) short term scientific mission award to Shaghayegh Basatvat.

Abbreviations

     
  • CC

    cumulus cells

  •  
  • FRT

    female reproductive tract

  •  
  • MAPK

    mitogen-activated protein kinases

  •  
  • NF-KB

    nuclear factor kappa-B

  •  
  • TLR

    toll-like receptor

  •  
  • TRIB

    tribbles

  •  
  • WOI

    window of implantation

Tribbles Pseudokinases on the Crossroads of Metabolism, Cancer, Immunity and Development: Held at The Aquincum Hotel, Budapest, 22–24 April 2015

References

References
1
Dobens
L.L.
Jr.
Bouyain
S.
Developmental roles of tribbles protein family members
Dev. Dyn.
2012
, vol. 
241
 (pg. 
1239
-
1248
)
[PubMed]
2
Kiss-Toth
E.
Tribbles: ‘puzzling’ regulators of cell signalling
Biochem. Soc. Trans.
2011
, vol. 
39
 (pg. 
684
-
687
)
[PubMed]
3
Hegedus
Z.
Czibula
A.
Kiss-Toth
E.
Tribbles: a family of kinase-like proteins with potent signalling regulatory function
Cell. Signal.
2007
, vol. 
19
 (pg. 
238
-
250
)
[PubMed]
4
Buday
L.
Tompa
P.
Functional classification of scaffold proteins and related molecules
FEBS J.
2010
, vol. 
277
 (pg. 
4348
-
4355
)
[PubMed]
5
Seher
T.C.
Leptin
M.
Tribbles, a cell-cycle brake that coordinates proliferation and morphogenesis during Drosophila gastrulation
Curr. Biol.
2000
, vol. 
10
 (pg. 
623
-
629
)
[PubMed]
6
Cunard
R.
Mammalian tribbles homologs at the crossroads of endoplasmic reticulum stress and Mammalian target of rapamycin pathways
Scientifica (Cairo)
2013
, vol. 
2013
 pg. 
750871
 
[PubMed]
7
Smith
S.M.
Moran
A.P.
Duggan
S.P.
Ahmed
S.E.
Mohamed
A.S.
Windle
H.J.
O'Neill
L.A.
Kelleher
D.P.
Tribbles 3: a novel regulator of TLR2-mediated signaling in response to Helicobacter pylori lipopolysaccharide
J. Immunol.
2011
, vol. 
186
 (pg. 
2462
-
2471
)
[PubMed]
8
Wei
S.C.
Rosenberg
I.M.
Cao
Z.
Huett
A.S.
Xavier
R.J.
Podolsky
D.K.
Tribbles 2 (Trib2) is a novel regulator of toll-like receptor 5 signaling
Inflamm. Bowel Dis.
2012
, vol. 
18
 (pg. 
877
-
888
)
[PubMed]
9
Ostertag
A.
Jones
A.
Rose
A.J.
Liebert
M.
Kleinsorg
S.
Reimann
A.
Vegiopoulos
A.
Berriel Diaz
M.
Strzoda
D.
Yamamoto
M.
, et al. 
Control of adipose tissue inflammation through TRB1
Diabetes
2010
, vol. 
59
 (pg. 
1991
-
2000
)
[PubMed]
10
Ghosh
S.
Karin
M.
Missing pieces in the NF-kappaB puzzle
Cell
2002
, vol. 
109
 
Suppl.
(pg. 
S81
-
S96
)
[PubMed]
11
Wu
M.
Xu
L.G.
Zhai
Z.
Shu
H.B.
SINK is a p65-interacting negative regulator of NF-kappaB-dependent transcription
J. Biol. Chem.
2003
, vol. 
278
 (pg. 
27072
-
27079
)
[PubMed]
12
Bronson
R.
Biology of the male reproductive tract: its cellular and morphological considerations
Am. J. Reprod. Immunol.
2011
, vol. 
65
 (pg. 
212
-
219
)
[PubMed]
13
Eppig
J.J.
Oocyte control of ovarian follicular development and function in mammals
Reproduction
2001
, vol. 
122
 (pg. 
829
-
838
)
[PubMed]
14
Edson
M.A.
Nagaraja
A.K.
Matzuk
M.M.
The mammalian ovary from genesis to revelation
Endocr. Rev.
2009
, vol. 
30
 (pg. 
624
-
712
)
[PubMed]
15
Fazeli
A.
Pewsey
E.
Maternal communication with gametes and embryos: a complex interactome
Brief. Funct. Genomics Proteomic
2008
, vol. 
7
 (pg. 
111
-
118
)
16
Lloyd
R.E.
Elliott
R.M.
Fazeli
A.
Watson
P.F.
Holt
W.V.
Effects of oviductal proteins, including heat shock 70 kDa protein 8, on survival of ram spermatozoa over 48 h in vitro
Reprod. Fertil. Dev.
2009
, vol. 
21
 (pg. 
408
-
418
)
[PubMed]
17
Georgiou
A.S.
Sostaric
E.
Wong
C.H.
Snijders
A.P.
Wright
P.C.
Moore
H.D.
Fazeli
A.
Gametes alter the oviductal secretory proteome
Mol. Cell. Proteomics
2005
, vol. 
4
 (pg. 
1785
-
1796
)
[PubMed]
18
Seytanoglu
A.
Georgiou
A.S.
Sostaric
E.
Watson
P.F.
Holt
W.V.
Fazeli
A.
Oviductal cell proteome alterations during the reproductive cycle in pigs
J. Proteome Res.
2008
, vol. 
7
 (pg. 
2825
-
2833
)
[PubMed]
19
Georgiou
A.S.
Snijders
A.P.
Sostaric
E.
Aflatoonian
R.
Vazquez
J.L.
Vazquez
J.M.
Roca
J.
Martinez
E.A.
Wright
P.C.
Fazeli
A.
Modulation of the oviductal environment by gametes
J. Proteome Res.
2007
, vol. 
6
 (pg. 
4656
-
4666
)
[PubMed]
20
Fazeli
A.
Maternal communication with gametes and embryos
Theriogenology
2008
, vol. 
70
 (pg. 
1182
-
1187
)
[PubMed]
21
Alminana
C.
Heath
P.R.
Wilkinson
S.
Sanchez-Osorio
J.
Cuello
C.
Parrilla
I.
Gil
M.A.
Vazquez
J.L.
Vazquez
J.M.
Roca
J.
, et al. 
Early developing pig embryos mediate their own environment in the maternal tract
PLoS One
2012
, vol. 
7
 pg. 
e33625
 
[PubMed]
22
Alminana
C.
Caballero
I.
Heath
P.R.
Maleki-Dizaji
S.
Parrilla
I.
Cuello
C.
Gil
M.A.
Vazquez
J.L.
Vazquez
J.M.
Roca
J.
, et al. 
The battle of the sexes starts in the oviduct: modulation of oviductal transcriptome by X and Y-bearing spermatozoa
BMC Genomics
2014
, vol. 
15
 pg. 
293
 
[PubMed]
23
Wassarman
P.M.
Jovine
L.
Litscher
E.S.
A profile of fertilization in mammals
Nat. Cell Biol.
2001
, vol. 
3
 (pg. 
E59
-
E64
)
[PubMed]
24
Dey
S.K.
Lim
H.
Das
S.K.
Reese
J.
Paria
B.C.
Daikoku
T.
Wang
H.
Molecular cues to implantation
Endoc. Rev.
2004
, vol. 
25
 (pg. 
341
-
373
)
25
Wang
H.
Dey
S.K.
Roadmap to embryo implantation: clues from mouse models
Nat. Rev. Genet.
2006
, vol. 
7
 (pg. 
185
-
199
)
[PubMed]
26
Granot
I.
Gnainsky
Y.
Dekel
N.
Endometrial inflammation and effect on implantation improvement and pregnancy outcome
Reproduction
2012
, vol. 
144
 (pg. 
661
-
668
)
[PubMed]
27
Tabibzadeh
S.
Babaknia
A.
The signals and molecular pathways involved in implantation, a symbiotic interaction between blastocyst and endometrium involving adhesion and tissue invasion
Hum. Reprod.
1995
, vol. 
10
 (pg. 
1579
-
1602
)
[PubMed]
28
Spencer
T.E.
Burghardt
R.C.
Johnson
G.A.
Bazer
F.W.
Conceptus signals for establishment and maintenance of pregnancy
Anim. Reprod. Sci.
2004
, vol. 
82-83
 (pg. 
537
-
550
)
29
Aflatoonian
R.
Tuckerman
E.
Elliott
S.L.
Bruce
C.
Aflatoonian
A.
Li
T.C.
Fazeli
A.
Menstrual cycle-dependent changes of toll-like receptors in endometrium
Hum. Reprod.
2007
, vol. 
22
 (pg. 
586
-
593
)
[PubMed]
30
Koga
K.
Mor
G.
Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy disorders
Am. J. Reprod. Immunol.
2010
, vol. 
63
 (pg. 
587
-
600
)
[PubMed]
31
Lamont
R.F.
The role of infection in preterm labour and birth
Hosp. Med.
2003
, vol. 
64
 (pg. 
644
-
647
)
[PubMed]
32
Mor
G.
Inflammation and pregnancy: the role of toll-like receptors in trophoblast-immune interaction
Ann. N.Y. Acad. Sci.
2008
, vol. 
1127
 (pg. 
121
-
128
)
33
Schuberth
H.J.
Taylor
U.
Zerbe
H.
Waberski
D.
Hunter
R.
Rath
D.
Immunological responses to semen in the female genital tract
Theriogenology
2008
, vol. 
70
 (pg. 
1174
-
1181
)
[PubMed]
34
Fahey
J.V.
Wright
J.A.
Shen
L.
Smith
J.M.
Ghosh
M.
Rossoll
R.M.
Wira
C.R.
Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture
Mucosal Immunol.
2008
, vol. 
1
 (pg. 
317
-
325
)
[PubMed]
35
Ghisletti
S.
Meda
C.
Maggi
A.
Vegeto
E.
17Beta-estradiol inhibits inflammatory gene expression by controlling NF-kappaB intracellular localization
Mol. Cell. Biol.
2005
, vol. 
25
 (pg. 
2957
-
2968
)
[PubMed]
36
Aboussahoud
W.
Aflatoonian
R.
Bruce
C.
Elliott
S.
Ward
J.
Newton
S.
Hombach-Klonisch
S.
Klonisch
T.
Fazeli
A.
Expression and function of Toll-like receptors in human endometrial epithelial cell lines
J. Reprod. Immunol.
2010
, vol. 
84
 (pg. 
41
-
51
)
[PubMed]
37
Mackern-Oberti
J.P.
Maccioni
M.
Breser
M.L.
Eley
A.
Miethke
T.
Rivero
V.E.
Innate immunity in the male genital tract: Chlamydia trachomatis induces keratinocyte-derived chemokine production in prostate, seminal vesicle and epididymis/vas deferens primary cultures
J. Med. Microbiol.
2011
, vol. 
60
 (pg. 
307
-
316
)
[PubMed]
38
Sanchez-Lopez
J.A.
Caballero
I.
Montazeri
M.
Maslehat
N.
Elliott
S.
Fernandez-Gonzalez
R.
Calle
A.
Gutierrez-Adan
A.
Fazeli
A.
Local activation of uterine toll-like receptor 2 and 2/6 decreases embryo implantation and affects uterine receptivity in mice
Biol. Reprod.
2014
, vol. 
90
 pg. 
87
 
[PubMed]
39
Montazeri
M.
Sanchez-Lopez
J.A.
Caballero
I.
Maslehat Lay
N.
Elliott
S.
Lopez-Martin
S.
Yanez-Mo
M.
Fazeli
A.
Activation of toll-like receptor 3 reduces actin polymerization and adhesion molecule expression in endometrial cells, a potential mechanism for viral-induced implantation failure
Hum. Reprod.
2015
, vol. 
30
 (pg. 
893
-
905
)
[PubMed]
40
Aboussahoud
W.
Bruce
C.
Elliott
S.
Fazeli
A.
Activation of toll-like receptor 5 decreases the attachment of human trophoblast cells to endometrial cells in vitro
Hum. Reprod.
2010
, vol. 
25
 (pg. 
2217
-
2228
)
[PubMed]
41
Dominguez
F.
Simon
C.
Quinonero
A.
Ramirez
M.A.
Gonzalez-Munoz
E.
Burghardt
H.
Cervero
A.
Martinez
S.
Pellicer
A.
Palacin
M.
, et al. 
Human endometrial CD98 is essential for blastocyst adhesion
PLoS One
2010
, vol. 
5
 pg. 
e13380
 
[PubMed]
42
Fraczek
M.
Kurpisz
M.
Inflammatory mediators exert toxic effects of oxidative stress on human spermatozoa
J. Androl.
2007
, vol. 
28
 (pg. 
325
-
333
)
[PubMed]
43
Meng
J.
Holdcraft
R.W.
Shima
J.E.
Griswold
M.D.
Braun
R.E.
Androgens regulate the permeability of the blood-testis barrier
Proc. Natl. Acad. Sci. U.S.A.
2005
, vol. 
102
 (pg. 
16696
-
16700
)
[PubMed]
44
Brisard
D.
Chesnel
F.
Elis
S.
Desmarchais
A.
Sanchez-Lazo
L.
Chasles
M.
Maillard
V.
Uzbekova
S.
Tribbles expression in cumulus cells is related to oocyte maturation and fatty acid metabolism
J. Ovarian Res.
2014
, vol. 
7
 pg. 
44
 
[PubMed]
45
Sung
H.Y.
Francis
S.E.
Crossman
D.C.
Kiss-Toth
E.
Regulation of expression and signalling modulator function of mammalian tribbles is cell-type specific
Immunol. Lett.
2006
, vol. 
104
 (pg. 
171
-
177
)
[PubMed]
46
Kiss-Toth
E.
Wyllie
D.H.
Holland
K.
Marsden
L.
Jozsa
V.
Oxley
K.M.
Polgar
T.
Qwarnstrom
E.E.
Dower
S.K.
Functional mapping and identification of novel regulators for the toll/interleukin-1 signalling network by transcription expression cloning
Cell. Signal.
2006
, vol. 
18
 (pg. 
202
-
214
)
[PubMed]
47
Deng
J.
James
C.H.
Patel
L.
Smith
A.
Burnand
K.G.
Rahmoune
H.
Lamb
J.R.
Davis
B.
Human tribbles homologue 2 is expressed in unstable regions of carotid plaques and regulates macrophage IL-10 in vitro
Clin. Sci. (Lond)
2009
, vol. 
116
 (pg. 
241
-
248
)
[PubMed]
48
Eder
K.
Guan
H.
Sung
H.Y.
Ward
J.
Angyal
A.
Janas
M.
Sarmay
G.
Duda
E.
Turner
M.
Dower
S.K.
, et al. 
Tribbles-2 is a novel regulator of inflammatory activation of monocytes
Int. Immunol.
2008
, vol. 
20
 (pg. 
1543
-
1550
)
[PubMed]