Interleukin-6: obstacles to targeting a complex cytokine in critical illness

Abstract

Circulating concentrations of the pleiotropic cytokine interleukin-6 (IL-6) are known to be increased in pro-inflammatory critical care syndromes, such as sepsis and acute respiratory distress syndrome. Elevations in serum IL-6 concentrations in patients with severe COVID-19 have led to renewed interest in the cytokine as a therapeutic target. However, although the pro-inflammatory properties of IL-6 are widely known, the cytokine also has a series of important physiological and anti-inflammatory functions. An adequate understanding of the complex processes by which IL-6 signalling occurs is crucial for the correct interpretation of IL-6 concentrations in the blood or lung, the use of IL-6 as a critical care biomarker, or the design of effective anti-IL-6 strategies. Here, we outline the role of IL-6 in health and disease, explain the different types of IL-6 signalling and their contribution to the net biological effect of the cytokine, describe the approaches to IL-6 inhibition that are currently available, and discuss implications for the future use of treatments such as tocilizumab in the critical care setting.

Figure 1

The pleiotropic effects of IL-6 IL-6, which consists of a four-helix bundle, is a master cytokine that exerts various biological effects. In addition to driving inflammation, fever, cytokinaemia, and tumorigenesis, IL-6 regulates metabolism, bone turnover, and haematopoiesis, and is essential for innate and adaptive immunity. In the liver, IL-6 contributes to tissue regeneration, lipid balance, and induction of the acute-phase response. This cytokine also promotes macrophage polarisation from the pro-inflammatory M1 state to an anti-inflammatory M2 phenotype and is required for the proliferation of the intestinal epithelium. IL-6=interleukin-6. RANKL=receptor activator of nuclear factor-κB ligand. VEGF=vascular endothelial growth factor.

Figure 2

The different types of IL-6 signalling In classical signalling, IL-6 binds the membrane-bound IL-6R to form an IL-6–IL-6R complex, which subsequently associates with gp130 to generate signal transduction via the JAK–STAT pathway. IL-6 can also bind to soluble forms of the IL-6R before converging on gp130 (trans-signalling), or be trans-presented from dendritic cells via their membrane-bound IL-6R to T cells (trans-presentation). In general terms, classical signalling causes the physiological, anti-inflammatory, and pro-resolution effects of IL-6, with the pathological effects of the cytokine mediated by trans-signalling and trans-presentation. Importantly, monoclonal antibodies against IL-6R, such as tocilizumab, do not discriminate between these signalling types, and instead block all IL-6 signalling. gp130=glycoprotein 130. IL-6=interleukin-6. IL-6R=interleukin-6 receptor. JAK=Janus kinase. sIL-6R=soluble interleukin-6 receptor. STAT=signal transducer and activator of transcription.

Figure 3

Pharmacological approaches to inhibiting the biological effects of IL-6 IL-6 can be inhibited directly at site 1, site 2, or site 3. The IL-6R can be blocked at the IL-6-binding site by the monoclonal antibodies tocilizumab, sarilumab, and vobarilizumab. The sgp130Fc olamkicept blocks IL-6 trans-signalling by neutralising the IL-6–sIL-6R complex before it can interact with cellular gp130. Within the cell, JAKs can be blocked by small-molecule kinase inhibitors of variable selectivity. IL-6=interleukin-6. IL-6R=interleukin-6 receptor. JAK=Janus kinase. STAT=signal transducer and activator of transcription. Tyk=non-receptor tyrosine-protein kinase.