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. 2020 Aug 7;11:1573. doi: 10.3389/fimmu.2020.01573

Figure 2.

Figure 2

Various Extracellular Cues Can Induce IL-27 Signaling In STAT-1, STAT-3, AND STAT-5 Dependent Manner. (A) IL-27 is heterodimeric cytokine comprised of p28 and Epstein-Barr virus-induced gene 3 (EBI3) subunits. (B) IL-27 exerts its specific effects in immune cells through binding to its receptor IL-27R (comprised of WSX-1/IL27Rα and gp130). (B) IL-27R is expressed by cells belonging to both innate and adaptive modules of the immune system. (C) The intracellular signaling is initiated when IL-27 binds to its receptor, and this triggers the signal flow through kinases JAK1, JAK2, and Tyrosine kinase (Tyk2) that phosphorylates the subsequent isoforms of STAT proteins (mainly STAT-1, STAT-3, STAT-4, and STAT-5 each of which, has restricted expression in various immune cells) and promote their dimerization and subsequent nuclear translocation. (D) The nuclear translocation of STAT-1 dimers can lead to the induction of IFN-γ signaling and transcription factor T-bet that induces Th1 cells. (E) However, nuclear translocation of STAT3-dimers leads to the synthesis of IL-10, CXCR3, cytotoxic T lymphocyte induction, GATA-3, RORγt that may promote Th2, Th17 responses (not necessarily under the effects of IL-27). (F) Signaling through STAT-5—its dimerization, nuclear translocation, and DNA binding through tyrosine phosphorylation—can lead to the upregulation of SOCS-1, E-cadherin, p53, Bcl-xL, p21, and Myc proteins. (G) The signals through IL-27R are carefully regulated in the cell via its intrinsic regulation through SOCS-1 and SOCS-3, maintaining a negative feedback loop. (H) The extracellular cues coming from extracellular ATP binding to purinergic receptors (P2R) in the case of inflammation and C5a binding to C5aR are antagonistic signals for IL-27 synthesis. (I) Broad effects of IL-27 relating to proliferation, in regulating cell cycle, neuroinflammation, metabolism, apoptosis, chromatin remodeling, and transcriptional control are mediated by STAT-1, STAT-3, and STAT-5 signaling pathways. (J) IL-27 stimulation in CD4+ T cells leads to their proliferation, expression of c-Myc, IL-10, ICAM, T-bet, IL-12Rβ1, IL-12Rβ2, MHC-II, and SOCS3. It also promotes the STAT1-, STAT3-dependent generation of IL-10 secreting Tr1 cells. IL-27 promotes CD8+ CTL generation, causes upregulation of T-bet, Eomesodermin (EOMES), and Granzyme-B. IL-27-induced modulation of host-pathogen relationships is an area described in this review in the context of protozoan parasite Leishmania.