Abstract
The IL-36 subfamily of cytokines has been recently described as part of the IL-1 superfamily. It comprises three pro-inflammatory agonists (IL-36α, IL-36β, and IL-36γ), their receptor (IL-36R), and one antagonist (IL-36Ra). Although expressed in a variety of cells, the biological relevance of IL-36 cytokines is most evident in the communication between epithelial cells, dendritic cells, and neutrophils, which constitute the common triad responsible for the initiation, maintenance, and expansion of inflammation. The immunological role of IL-36 cytokines was initially described in studies of psoriasis, but novel evidence demonstrates their involvement in further immune and inflammatory processes in physiological and pathological situations. Preliminary studies have reported a dynamic expression of IL-36 cytokines in the female reproductive tract throughout the menstrual cycle, as well as their association with the production of immune mediators and cellular recruitment in the vaginal microenvironment contributing to host defense. In pregnancy, alteration of the placental IL-36 axis has been reported upon infection and pre-eclampsia suggesting its pivotal role in the regulation of maternal immune responses. In this review, we summarize current knowledge regarding the regulatory mechanisms and biological actions of IL-36 cytokines, their participation in different inflammatory conditions, and the emerging data on their potential role in normal and complicated pregnancies.
Highlights
Pregnancy requires a unique immune program in which the conceptus must be tolerated and supported by the maternal organism, even though half of its genetic characteristics derive from the father
It begins with myeloid differentiation primary response 88 (MyD88) activation followed by IL-1 receptor associated kinase (IRAK) and TNF receptor-associated factor 6 (TRAF-6), leading to the degradation of IkB kinase complex (IKK) and release of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), which in turn favors the expression of pro-inflammatory mediators [65]
Recombinant IL-36α facilitates NLRP3 inflammasome activation in renal tubular epithelial cells, macrophages, and dendritic cells as well as enhances DC–induced T cell proliferation and Th17 differentiation. These results indicate a synergistic interaction between the IL-36 and the IL-23/IL-17 axis in the amplification of inflammatory disorders [124]
Summary
Pregnancy requires a unique immune program in which the conceptus must be tolerated and supported by the maternal organism, even though half of its genetic characteristics derive from the father. Medawar was the first to notice that, in immunological terms, the fetus has a similar condition as a semi-allogenic graft This observation was based on the assumption that the placenta expresses paternal antigens and, under normal immunological conditions, should be rejected [1]. Numerous immunological processes in pregnancy and the placenta have been studied and described, many immune mechanisms acting during the normal development of pregnancy or the menstrual cycle are still not fully understood. Several molecules such as cytokines, growth factors and hormones actively participate in these processes. They modulate a non-pathological form of inflammation in pivotal stages such as endometrial decidualization, embryo implantation, and induction of childbirth
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