IL-27: a double agent in the IL-6 family

Abstract

The cytokine interleukin (IL)-6 is a major therapeutic target for the treatment of various inflammatory and autoimmune diseases. While IL-6 receives considerable attention in studies of innate and adaptive immunity, the IL-6-related family member IL-27 is recognized increasingly for its effects on cellular proliferation, differentiation and leucocyte effector functions. Both cytokines activate responses in myeloid and stromal tissue cells, where they direct the transition from innate to adaptive immunity. However, they are identified frequently as lymphokines that control responses in T cells and B cells. In this regard, IL-27 often opposes the action of IL-6. Here, we will review the role of IL-6 and IL-27 in inflammation, with a particular focus on inflammatory arthritis, and discuss their importance in the diagnosis, stratification and treatment of autoimmune disease.

Keywords: arthritis; cytokine receptors; cytokines; inflammation; rheumatoid arthritis.

Figure 1

The biological relationship between interleukin (IL)‐6 and IL‐27. The illustration shows the composition of the IL‐6 and IL‐27 receptor complexes, and identifies the signal transducer and activator of transcription (STAT) factors triggered by both cytokines. Note the inclusion of gp130 in both receptors, and preferential induction of STAT1 and STAT3 activity (bold text). For the IL‐6 receptor cassette the reader should note the various IL‐6 and IL‐6R blocking therapies currently in clinical development or clinical utility. Proteins displayed in the orange box indicate biological entities that have been reported to engage with the IL‐6 receptor, albeit at low affinity. Cytokines listed in the blue box showcase the protein composition of IL‐27 related heterodimeric cytokines. Common subunits are colour‐coded. The IL‐6 : sIL‐6R (and that of p28 : sIL‐6R) complex is not stable, however, and the cytokine‐receptor undergoes association and reassociation (indicated by the + symbol).

Figure 2

The functional properties of interleukin (IL)‐6 and IL‐27. The biological properties of IL‐6 and IL‐27 have been categorized broadly under the terms ‘inflammation’, ‘homeostasis’ and ‘wellbeing’. Defined activities have been listed for each category and the heat‐map identifies the relative contribution of IL‐6 and IL‐27 to each of these processes. The definition of the colour‐coding is listed. It should be noted that IL‐6 and IL‐27 may regulate similar or distinct outcomes in each process and the reader is referred to the text and review papers relevant to IL‐6 or IL‐27 (references 3, 5).

Figure 3

Immunomodulatory action of interleukin (IL‐27) and the interface with IL‐6. IL‐27 and IL‐6 together co‐ordinate adaptive immune responses, often with opposing biological outcomes. In an inflammatory microenvironment, and supported by accessory cytokines, IL‐6 can promote the differentiation of T helper type 1 (Th1), Th2, Th22 and Th17 cells. In contrast, IL‐27 counteracts the IL‐6‐driven expansion of Th17 cells and inhibits the development of Th2 and Th22 cells. However, IL‐6 and IL‐27 can both promote the secretion of IL‐10 in a number of effector T cell subsets, and can drive the production of IL‐21 in T helper cells. IL‐27 drives immunosuppressive effector characteristics in T cells, including the expression of the immune check‐points programmed death ligand 1 (PD‐L1), programmed death 1 (PD‐1) and cytotoxic T lymphocyte antigen‐4 (CTLA‐4). In contrast to the inhibitory action of IL‐6 on regulatory T cells (T_reg cells), IL‐27 promotes the development of IL‐10‐producing T‐bet⁺CXCR3⁺ T_reg cells and Tr1 cells. IL‐27 also has immunosuppressive roles at the dendritic cell (DC) : T cell synapse; for example, through promoting expression of PD‐L1 on DCs and inhibiting major histocompatibility complex (MHC)‐I expression. Boxed areas highlight opposing roles of IL‐27 and IL‐6. Figure adapted from Yoshida et al. (reference 3).