IL-27 Signaling

Interleukin-27 (IL-27) is a cytokine belonging to the IL-6/IL-12 family, characterized by its dual role in immunomodulation, encompassing both pro-inflammatory and anti-inflammatory attributes. The composition of IL-27 involves a heterodimeric configuration, consisting of the α-subunit IL-27p28, a protein structured with a four-α-helix bundle, and the β-subunit Epstein-Barr virus-induced gene 3 (EBI-3). This complex binds to the IL-27 receptor, a composite assembly comprising the gp130 subunit and the IL-27RA subunit. Notably, various immune cell types, including T cells, macrophages, and dendritic cells, express the IL-27 receptor (Ref.1).

The interaction between IL-27 and its receptor elicits consequential signaling cascades involving Janus kinase (JAK) and signal transducer and activator of transcription (STAT), as well as mitogen-activated protein kinase (MAPK) pathways. Specifically, the IL-27 receptor's intracellular domain encompasses Box 1 motifs, which act as docking sites for JAK1/2. Subsequent activation of these kinases initiates downstream signaling through STAT1 and STAT3 pathways. The primary involvement of the STAT1/STAT3 pathway lies in the differentiation of T helper 1 (Th1) and Type 1 regulatory T (Tr1) cells, respectively. Activation of STAT1 contributes to Th1 cell differentiation through mechanisms involving T-bet activation and the upregulation of membrane ICAM-1. This, in turn, fosters interactions with LFA-1 and subsequent ERK signaling. An alternative pathway leading to T-bet activation is mediated by GADD45, culminating in p38/MAPK activation. These pathways collectively lead to the secretion of interferon-gamma (IFN-γ). Notably, the regulatory loop involving suppressor of cytokine signaling 3 (SOCS3) operates as a negative feedback mechanism to control Th1 response (Ref.2 and 3).

In parallel, IL-27 signaling prompts the differentiation of Tr1 cells by activating transcription factors AHR and c-Maf, both of which are associated with IL-10-related functions. Moreover, an alternate pathway involving EGR2 and BLIMP1 contributes to this differentiation process (Ref.3).

One of the pronounced immunoregulatory attributes of IL-27 is its ability to suppress Th17 responses while concurrently promoting the differentiation of T regulatory cells. Activation of T cells by IL-27 result in the secretion of the anti-inflammatory cytokine IL-10 that further mitigates the overall inflammatory response. These multifaceted properties position IL-27 as an appealing pharmacological target for managing conditions characterized by T cell-mediated inflammatory responses (Ref.4).