Making sense of IL-6 signalling cues in pathophysiology

Abstract

Unravelling the molecular mechanisms that account for functional pleiotropy is a major challenge for researchers in cytokine biology. Cytokine-receptor cross-reactivity and shared signalling pathways are considered primary drivers of cytokine pleiotropy. However, reports epitomized by studies of Jak-STAT cytokine signalling identify interesting biochemical and epigenetic determinants of transcription factor regulation that affect the delivery of signal-dependent cytokine responses. Here, a regulatory interplay between STAT transcription factors and their convergence to specific genomic enhancers support the fine-tuning of cytokine responses controlling host immunity, functional identity, and tissue homeostasis and repair. In this review, we provide an overview of the signalling networks that shape the way cells sense and interpret cytokine cues. With an emphasis on the biology of interleukin-6, we highlight the importance of these mechanisms to both physiological processes and pathophysiological outcomes.

Keywords: Jak-STAT signalling; STAT transcription factors; arthritis; cytokine receptors; cytokines; epigenetics; inflammation; interleukin; microRNA; pathophysiology.

Fig. 1

Modes of IL‐6 signalling and determinants of IL‐6 responsiveness. The boxed cartoon representations show the three modes of IL‐6 receptor signalling. Subunits of the cytokine receptor cassette are colour coded as indicated. PM denotes plasma membrane, and shows the subunits bound to the cell surface in each signalling mode. The wider panel shows how the signalling intermediates associated with IL‐6 receptor signalling engage with gp130 (tyrosine residues based on the human gp130 sequence are designated) and contribute to the cellular activities of IL‐6. Note, the expression of STAT‐inducible negative feedback inhibitors, which act to limit the protracted activation of the receptor complex.

Fig. 2

Relationship between STAT1 and STAT3 and IL‐6 responsiveness. (A) Jak‐STAT signalling in response to IL‐6 triggers activation of the latent transcription factors STAT1 and STAT3. The dimerization and translocation of these proteins to the nucleus targets genomic promoter and enhancer sites that include consensus DNA motifs for STAT transcription factor binding (e.g. IFN‐stimulated responsive elements; ISRE, IFNγ‐activated sequence; GAS). While STAT1 and STAT3 engage specific gene targets, with STAT1 controlling various interferon‐like responsive genes (e.g. Irf1, Stat1 in CD4⁺ T cells) and STAT3 governing responses linked with metabolism, proliferation, survival, and functional identity. These often work at proximal and distal promoter sites. Extending studies originating from investigations in cancer, there is now increasing evidence supporting the role of STAT1 in shaping the transcriptional output of STAT3. (B) The balance of STAT1 and STAT3 activity is therefore instrumental in determining the transcriptional output of IL‐6 and regulatory mechanisms, including the action of protein phosphatases act to moderate or fine‐tune the cell response to IL‐6.

Fig. 3

MicroRNA targeting of the IL‐6 receptor cassette. MicroRNAs with selectivity for components of the IL‐6 receptor and downstream signalling intermediates are shown. The dashed lines identify a potential influence on sIL‐6R bioavailability through the control of IL‐6R.

Fig. 4

The complexities of IL‐6 biology in immune‐mediated disease. A summary of IL‐6 involvements in immune‐mediated inflammatory disease. Using rheumatoid arthritis as an example, the figure showcases the major contributions of IL‐6 to systemic immune outcomes, comorbidity, and reactions relevant to local pathology in the inflamed joint.