IL-36 Cytokines: Regulators of Inflammatory Responses and Their Emerging Role in Immunology of Reproduction

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.

Keywords: IL-1 superfamily; IL-36 cytokines; inflammation; pregnancy; uterus.

Figure 1

IL-1 superfamily. The IL-1 superfamily is comprised of 11 cytokines with pro-inflammatory or anti-inflammatory activity divided into IL-1, IL-18, and IL-36 subfamilies. All members, except IL-1Ra, are synthesized as long precursor proteins, which are proteolytically cleaved by the indicated enzymes to generate their active mature proteins.

Figure 2

IL-36 signaling pathway. IL-36α, IL-36β, and IL-36γ bind to IL-36R leading to its dimerization with IL-1RAcP. The active receptor triggers intracellular signaling cascades involving MyD88, IRAK, and MAPK to induce NF-kB- and AP-1-dependent expression of pro-inflammatory cytokines, chemokines, and secondary mediators of the inflammatory response. IL-36Ra and IL-38 bind to IL-36R inhibiting receptor dimerization and activation.

Figure 3

Origin and effects of IL-36 cytokines on different cell types. IL-36 cytokines are released by epithelial cells and processed by neutrophil-derived proteases to generate their active forms. The activated cytokines stimulate dendritic cells to enhance pro-inflammatory mediators responsible for several cellular effects in innate and adaptive immune responses. Some processes regulated on immune and non-immune cells are indicated. Note that there is still no data for trophoblast cells.

Figure 4

Illustrative description of the pro-inflammatory (red line) and anti-inflammatory (blue line) balance and IL-36 expression during pregnancy. Deregulated inflammatory reactions (red dotted line) may occur at any time in pregnancy and may overlap with each other. Depending on the stage, distinct complications can arise.