Journal of Clinical and Cellular Immunology
Open Access

The JAK-STAT Signaling Pathway: A Novel Therapeutic Target for Unexplained Recurrent Implantation Failures

Author info »

Introduction

Unexplained recurrent implantation failures is defined as the repeated failures of embryos to implant due to a failure of the immunological crosstalk between the transferred embryo and the endometrium in at least three or more assisted reproductive therapy cycles following the transfer of quality embryos in a healthy woman less than 40 years [1,2]. Implantation of the embryo is the rate limiting step in assisted reproductive therapy [3-8]. The mechanism underlying a failed implantation in repeated assisted reproductive therapy cycle could be considered similar to an alloimmune rejection since the embryo is a semiallograft [9]. Cytokines mediate immune cell interactions during allograft rejections. The embryo during implantation has been described as bathing in a sea of cytokines [10]. Perturbations in the cytokine crosstalk during the window of implantation are therefore considered a major etiology in unexplained recurrent implantation failures. Cytokines has been shown to control the expression of adhesion, anti-adhesion, secretion of endocrine molecules as well as the activation of immune cells at the embryo-endometrial interface during the implantation process [11,12].

Subjects and Methods

The JAK-STAT signaling pathway

The Janus kinases (JAK) are part of the tyrosine kinase group of enzymes of which four members have been identified: JAK1, JAK2, JAK3 and TYK2 (Tyrosine kinase 2). The signal transducers and activation of transcription (STAT) on the other hand are family of transcription factors which includes 1-5a, 5b and 6 [13]. The JAK-STAT signaling pathway is a pleiotropic cascade that regulates cytokine function [14]. The current model of JAK-STAT signaling holds that the binding of cytokines to their receptors activates JAK which in turn phosphorylates an intracellular domain of the receptor leading to recruitment and phosphorylation of a STAT [14]. Phosphorylated STAT form dimers which then translocate into the nucleus to activate the expression or repression of target genes. The regulation of the JAK/STAT signaling is essential for crosstalk among various cytokine signaling pathways involved in immune cell activation. A crosstalk refers to mutual influences of signals generated from different pathways. Crosstalk occurs at all levels between different immune cells, cytokines and intracellular signaling pathways. The extent of crosstalk during inflammation is not known [15]. JAK function has been shown to be important for the crosstalk of Src-kinase cascade, the Ras-MAP kinase pathway, the P13k-AKT pathway as well as the ERK pathways during an immune response. Aberrations in JAK activity could also lead to perturbations in one or more of the above mentioned pathways resulting in diseases [16].

Cytokines, JAK-STAT signaling and implantation failures

Though cytokines are produced by nearly all immune cells, only a few cytokines particularly the helper T-cell produced cytokines has received prominent importance in our stride to understanding the mechanism of unexplained recurrent implantation failures [17]. This is because the helper T (TH) cells were identified to play a key role of deciding the nature of the immune response as either inflammatory or antiinflammatory. In effect, if a naïve helper T (THO) cell encounters a paternally derived antigen of the implanting embryo, it undergoes proliferation and differentiation into four distinct populations of cells namely the TH1, TH2, TH17 and Treg cells. Each cell population produces a unique set of cytokines [18,19]. The profile of cytokines produced in response to the implanting embryo determines the nature of the immune response to the embryo as either inflammatory or antiinflammatory [19]. Based on this, embryo rejection and resultant implantation failures observed in embryo transfer cycles is considered a helper T-cell phenomenon in which the TH1, and TH17 cytokines has an inflammatory effect while the opposing TH2 and Treg cell cytokines exerts an antiinflammatory effect on the embryo[19,20]. It is therefore proposed that a balance between the antagonist T-cell populations and their respective cytokines is the basis for immunological tolerance failures in embryo implantation process during assisted reproductive therapy cycles. In view of this, unexplained recurrent implantation failures may be considered a T-Cell disorder. Consequently, the role of the JAKSTAT pathway in the regulation of TH cells is well established. STAT 2 and 4 are important for TH1 signaling, STAT 6 is important for TH2 signaling, STAT 3 is important for TH17 signaling while STAT 5 functions in Treg cell signaling (Table 1) [21,22].

Table 1: Signal transducer and activator of transcription (STAT) for different cytokine signaling.

IL-6/JAK/STAT 3: A therapy target model

Members of the gp130 signaling cytokines have been implicated in implantation failures through their interactions with interleukin 6 (IL-6). The gp130 cytokines describes the various cytokines that utilizes the gp130 signaling pathway. This includes Interleukin-6 (IL-6), Interleukin-11(IL-11), Cardiotrophin (CT) 1, Ciliary Neutropic Factor (CNTF), Oncostatin M (OSM) and Cardiotropin-Like Cytokine/ Cytokine-Like Factor (CLC-CLF) [23]. IL-6 binds to the IL-6R on target cells, the IL-6/IL-6R complex activates the gp130 triggering its dimerization and subsequent activation of STAT 3 phosphorylation by JAK [24]. This classical signaling pathway is activated during early immune response and may be responsible for the activation of various immune cells that act locally at the maternal-conceptus interface during the window of implantation. In view of the above system, we suggest that a therapeutic strategy targeting the IL-6/JAK/STAT 3 pathway using their inhibitors may stimulate the development of a suitable therapy for unexplained recurrent implantation failures. A major challenge to this will be a stimulation of adverse effects unrelated to the target therapeutic actions by the JAK-STAT inhibitors. However, the generation of a selective inhibitor of JAK 3 will be an effective approach to addressing this. This is because studies has shown that patients with JAK 3-SCID remain healthy after successful transplantation. This implies that JAK 3 deficiency results in mere immunodeficiency but not diverse immunological defects [25]. A highly specific JAK3 inhibitor will surely have very limited side effect. Many JAK inhibitors (JAKinhibs) and STAT inhibitors (STATinhibs) are currently under preclinical evaluations while some are passing clinical trials and FDA approval (Table 2).

Table 2: A number of JAK and STAT inhibitors are explored for treatment of diseases.

Conclusion

JAK-STAT pathway has a critical role in the regulation of the immune system particularly cytokine crosstalk. Since perturbations in the JAK-STAT pathway and their regulators may lead to unexplained recurrent implantation failures, targeting their signaling may lead to development of novel strategies for the treatment of unexplained recurrent implantation failures.

Transparency

Declaration of funding

This was an independent non-sponsored trial.

Declaration of financial/other relationships

MM is an employee of Cantabria Lab, Difa Cooper. The other author (MP) reports no conflicts of interest.

Contribution statement

MP conducted the trial performing visits and instrumental evaluations. MM was involved in study protocol design. Both authors contributed toward data analysis, drafting and critically revising the paper and agree to be accountable for all aspects of the work.

Acknowledgment

None reported.

References

1. Timeva T, Atanas S, Stanimir. Recurrent implantation failure: The role of the endometrium. J Reprod Infertil. 2004; 15:173-183.
2. Siristatids C, Vogiatzi P, Branchnis N, Liassiduo A, Illiodromit Z, Bettochi S et al. Micro RNAs in assisted reproduction and their potential role in IVF failure. In Vivo. 2015; 29:169-175.
3. Comins BA, Garcia SA, Prado DNN, Fuente DL, Alonso J, Ramón SS, et al. Evidence-based update: Immunological evaluation of recurrent implantation failure. Reprod Immunol Open Acc. 2016; 1:1-8.
4. Ly KD, Aziz N, Safi J, Agarwal A. Evidence-based management of infertile couples with repeated implantation failures following IVF. Curr Women’s Health Rev. 2010; 6:200-218.
5. Koot YEM, Hoof VSR, Boomsma MC, Leenan VD, Koerkamp MJAG. An endometrial gene expression signature accurately predicts recurrent implantation failures after IVF. Sci Rep. 2016; 6:1-12.
6. Khalife D, Ghazeeri G. Recurrent implantation failure and low molecular weight heparin. Open J Obstet Gynecol. 2018; 8:146-162.
7. Bakshi R, Jha B, Prakash. The impact of endometrial scratching on the outcome of in vitro fertilization cycles: A prospective study. Fertil Sci Res. 2016; 3:8-86.
8. Shufaro Y, Schenker JG. Implantation failure, etiology, diagnosis and treatment. IJIFM. 2011; 2:1-7.
9. Nakagawa K, Kwak-Kim J, Ota K, Kuroda K, Hisano M, Sugiyama R, et al. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood Th1/Th2 cell ratios. Am J Reprod Immunol. 2015; 73:353-361.
10. Wegmann TG, Lin H, Guilbert I, Mosmann TR. Bidirectional Cytokine interactions in the maternal-fetal relationship is successful pregnancy a TH2 phenomenon? Immunol Today. 1993; 14:353-356.
11. Simon CJ, Martin C, Pellicer A. Paracrine regulators of implantation. Baillieres Best Pract Res Clin Obstet Gynecol. 2000; 14:815-826.
12. Bowen JM, Chamley L, Mitchel MD, Keel JA. Cytokine of the placenta and extra placental membranes: Biosynthesis, secretion and roles in establishment of pregnancy in women. Placenta. 2002; 23:239-256.
13. Kubler P. Janus Kinase inhibitors: Mechanism of action. Exp Clin Pharmacol. 2014; 37:154-157.
14. Chuang Py, He JC. JAK/STAT signaling in renal disease. Kidney Int. 2010; 78:231-234.
15. Schmitz LM, Weber A, Roxlau T, Gaestel M, Kracht M. Signal integration, crosstalk mechanisms and networks in the function of inflammatory cytokines. BBA Mol Cell Res. 2011; 1813:2165-2175.
16. Sushil RG, Premkumar RE. Janus Kinases: Components of multiple signaling pathways. Oncogene. 2000; 19:5662-5679.
17. Ogbuabor AO, Achukwu PU, Ufelle SA, Ogbuabor DC, Nebo EE. The cytokine network: An integrated approach to understanding the mechanism of unexplained recurrent implantation failures. J Cytokine Biol. 2019; 4:130.
18. Wang T, Secombes CJ. The cytokine networks of adaptive immunity in fish. Fish Shellfish Immunol. 2013; 35:1703-1718.
19. Ginsburg ES, Xiao L, Gargiulo RA, Kung F, Politch JA. Successful in vitro fertilization embryo transfer. Fertil and Steril. 2005; 83:1-6.
20. Azad M, Sara K, Bahia NJ, Zahra K, Gharesi FB. T helper cell subsets and related cytokines in infertile women undergoing in vitro fertilization before and after seminal plasma exposure. Clin Exp Reprod Med. 2017; 44:214-223.
21. Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M, et al. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell commun and signaling. 2017; 15:23.
22. Nan Y, Wu C, Zhang YJ. Interplay between janus kinase/signal transducer and activator of transcription signaling activated by Type 1 interferons and Viral Antagonism. Front Immunol. 2017; 8:1-17.
23. Dimitriads E, White CA, Jones RL, Salamonsen LA. Cytokines, Chemokines and growth factors in endometrium related to implantation. Human Reprod Update. 2005; 11:613-630.
24. Wang SW, Sun YM. The IL-6/JAK/STAT 3 pathway: Potential therapeutic strategies in treating colorectal cancer (Review). Int J Oncology. 2014; 44:1032-1040.
25. Shea JJO. Targeting the JAK/STAT pathway for immunosuppression. Ann Rheum Dis. 2004; 63:ii67-ii71.