Structural Understanding of Interleukin 6 Family Cytokine Signaling and Targeted Therapies: Focus on Interleukin 11

Abstract

Cytokines are small signaling proteins that have central roles in inflammation and cell survival. In the half-century since the discovery of the first cytokines, the interferons, over fifty cytokines have been identified. Amongst these is interleukin (IL)-6, the first and prototypical member of the IL-6 family of cytokines, nearly all of which utilize the common signaling receptor, gp130. In the last decade, there have been numerous advances in our understanding of the structural mechanisms of IL-6 family signaling, particularly for IL-6 itself. However, our understanding of the detailed structural mechanisms underlying signaling by most IL-6 family members remains limited. With the emergence of new roles for IL-6 family cytokines in disease and, in particular, roles of IL-11 in cardiovascular disease, lung disease, and cancer, there is an emerging need to develop therapeutics that can progress to clinical use. Here we outline our current knowledge of the structural mechanism of signaling by the IL-6 family of cytokines. We discuss how this knowledge allows us to understand the mechanism of action of currently available inhibitors targeting IL-6 family cytokine signaling, and most importantly how it allows for improved opportunities to pharmacologically disrupt cytokine signaling. We focus specifically on the need to develop and understand inhibitors that disrupt IL-11 signaling.

The IL6-like Cytokine Family: Role and Biomarker Potential in Breast Cancer

“…nisms for complex formation, evidencing the biological specificity for each ligand-receptor pair [28]. Consistently across all family members, site II is always the binding site for the shared receptor gp130/IL6ST.…”

“…A recent study has reported on the different mecha- Site I, used only by some cytokines, is a binding site for non-signalling receptors only (e.g., IL6R for IL6 or IL11R for IL11). A recent study has reported on the different mechanisms for complex formation, evidencing the biological specificity for each ligandreceptor pair [28]. Consistently across all family members, site II is always the binding site for the shared receptor gp130/IL6ST.…”

IL-6 Reduces Mitochondrial Replication, and IL-6 Receptors Reduce Chronic Inflammation in NAFLD and Type 2 Diabetes

“…Plasma IL-11 levels were negatively correlated with BAX protein production in liver biopsies. IL-11 is also soluble [ 22 , 28 ] and is blocked by sgp130 binding. How sgp130 affects the pathways triggered by these cytokines and how these pathways influence the effects of sgp130 deserve further study.…”

miR‐10396b‐3p inhibits mechanical stress‐induced ligamentum flavum hypertrophy by targeting IL‐11

“…IL-11, a major member of the IL-6 proteins family, was involved in the production of ECM in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes. 26 F I G U R E 5 IL-11 promotes fibrosis expressions by up-regulating collagen I and collagen III in LF fibroblasts. A, The quantitative real-time PCR analysis showing mRNA levels of fibrosis-related genes (COL1A2 and COL3A1) in LF cells at 12 hours and 24 hours (n = 4).…”