The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature

Abstract

Recurrent implantation failure (RIF) is a multifactorial condition affecting 10-15% of in vitro fertilization (IVF) couples. Data suggest that functional dysregulation of the endometrial immune system constitutes one of the main pathophysiological mechanisms leading to RIF. The aim of this article is to provide a thorough presentation and evaluation of the role of interleukins (ILs) in the pathogenesis of RIF. A comprehensive literature screening was performed summarizing current evidence. During implantation, several classes of ILs are secreted by epithelial and stromal endometrial cells, including IL-6, IL-10, IL-12, IL-15, IL-18, and the leukemia inhibitory factor. These ILs create a perplexing network that orchestrates both proliferation and maturation of uterine natural killer cells, controls the function of regulatory T and B cells inhibiting the secretion of antifetal antibodies, and supports trophoblast invasion and decidua formation. The existing data indicate associations between ILs and RIF. The extensive analysis performed herein concludes that the dysregulation of the ILs network indeed jeopardizes implantation leading to RIF. This review further proposes a mapping of future research on how to move forward from mere associations to robust molecular data that will allow an accurate profiling of ILs in turn enabling evidence-based consultancy and decision making when addressing RIF patients.

Keywords: decidua; embryo implantation; in vitro fertilization (IVF); infertility; interleukins; recurrent implantation failure (RIF); uterus.

Figure 1

Molecular action of leukemia inhibitory factor during embryo implantation and pregnancy establishment. LIF: leukemia inhibitory factor; KLF12: Krüppel-like factor 12; INF-γ: interferon-gamma; LIF-R: leukemia inhibitory factor receptor; gp130: glycoprotein 130; IGF1: insulin-like growth factor 1; TLR: toll-like receptor; VEGF: vascular endothelial growth factor; Wnt: Wingless/Int; JAK: Janus kinases; STAT3: signal transducer and activator of transcription factor 3.

Figure 2

Molecular action of IL-6 and other anti-inflammatory cytokines during embryo implantation and pregnancy establishment. IL-6: interleukin 6; hCG: human chorionic gonadotropin; IL-6R: interleukin 6 receptor; TGF-β: transforming growth factor-beta; JAK: Janus kinases; STAT3: signal transducers and activators of transcription; MAPKs: mitogen-activated protein kinases.

Figure 3

Molecular action of IL-1β and other pro-inflammatory cytokines during embryo implantation and pregnancy establishment. IL-1β: interleukin 1 beta; uNK: uterine natural killer cells; MMPs: matrix metalloproteinases; cAMP: cyclic adenosine monophosphate; COX2: cyclooxygenase-2; PGE2: prostaglandin E2; TNF-α: tumor necrosis factor-alpha; INF-γ: interferon-gamma; GM-CSF: granulocyte-macrophage colony-stimulating factor; Th: T helper cells; Treg: T regulatory cells.

Figure 4

A summary of the role of interleukins on the events entailed in recurrent implantation failure (RIF) pathogenesis.