Unravelling the broader complexity of IL-6 involvement in health and disease

•IL-6 controls tissue and immune homeostasis in both health and disease.•The IL-6 signalling cassette is complex and regulated at multiple levels.•IL-6 affects metabolism, neuroendocrine functions, pain, and mental health.•Specific genetic mutations identify important roles for IL-6 in human physiology.•Biological drugs against IL-6 inhibit target all aspects of IL-6 bioactivity. The classification of interleukin-6 (IL-6) as a pro-inflammatory cytokine undervalues the biological impact of this cytokine in health and disease. With broad activities affecting the immune system, tissue homeostasis and metabolic processes, IL-6 displays complex biology. The significance of these involvements has become increasingly important in clinical settings where IL-6 is identified as a prominent target for therapy. Here, clinical experience with IL-6 antagonists emphasises the need to understand the context-dependent properties of IL-6 within an inflammatory environment and the anticipated or unexpected consequences of IL-6 blockade. In this review, we will describe the immunobiology of IL-6 and explore the gamut of IL-6 bioactivity affecting the clinical response to biological drugs targeting this cytokine pathway.