Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer

Abstract

The interleukin-6 (IL-6) family of cytokines consists of oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological significance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer, and review therapeutic strategies designed to manipulate these cytokines in disease. [H1] IntroductionCytokines contribute to all aspects of human biology and have evolved to enable the sensing and interpretation of environmental cues relevant to the maintenance of normal host physiology 1 . Although these secretory proteins are best known for their role as custodians of immune homeostasis and the inflammatory response to infection, trauma or injury, their diverse functions also affect embryonic development, cognitive function and behaviour, tissue integrity, and ageing. In this regard, cytokines often display pleiotropic or overlapping functional properties 1 .The interleukin-6 (IL-6) cytokine family comprises IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1), and among all cytokine families it arguably displays the highest degree of functional pleiotropy and redundancy in eliciting responses relevant to health and disease 2 . Members of this family play prominent roles in chronic inflammation, autoimmunity, infectious disease and cancer (BOX 1), where they often act as diagnostic or prognostic indicators of disease activity and response to therapy 1,3-6 . Moreover, IL-6 family cytokines are now viewed as major therapeutic targets for clinical intervention [3][4][5][6][7][8][9] . This is epitomized by the treatment of chronic immune-related conditions, such as inflammatory arthritis, giant cell arteritis and Castleman's disease, with drugs that target IL-6 5,10-12 . In this Review, we will draw on recent advances to provide a timely update on the biology of IL-6 family cytokines and their clinical potential as therapeutic targets or disease modifiers in autoimmunity, inflammation, infection and cancer. [H1] What constitutes IL-6 family membership?IL-6 remains the archetypal member of the IL-6 cytokine family, and regulates a diverse array of functions relevant to haematopoiesis, tissue homeostasis, metabolism and immunity (BOX 1 &Jones & Jenkins, 2018 Nature Reviews ImmunologyThe ...

A directly GP130‐targeting small molecule ameliorates collagen‐induced arthritis (CIA) by inhibiting IL‐6/GP130 signalling and Th17 differentiation

“…Classical IL‐6R signalling activity is mediated through the membrane‐bound IL‐6R complex and is limited to cells expressing both IL‐6Rα and gp130. In contrast, the IL‐6 trans‐signalling refers to processes including IL‐6 binding to a soluble IL‐6Rα (SIL‐6R) that maintains the circulating half‐life of IL‐6 and increases its bioavailability . IL‐6 trans‐signalling is now considered the main player in local IL‐6‐driven pathology and the hallmarks of inflammatory or degenerative forms of arthritis are primarily regulated by STAT3.…”

ADAM 17 selectively activates the IL ‐6 trans‐signaling/ ERK MAPK axis in KRAS ‐addicted lung cancer

“…Furthermore, we refer to the prospect of targeting ADAM17 versus sIL‐6R‐dependent trans‐signaling in LAC, the latter with existing antibody‐mediated therapeutic strategies. The rationale to target trans‐signaling in disease, rather than the “classic” IL‐6 signaling mode which is dependent on the membrane‐bound IL‐6R, is based on the opposing roles of IL‐6 in either maintaining homeostatic processes (e.g., regulation of B‐cell function, the acute phase response, and hematopoiesis), or conversely, driving chronic disease states such as inflammation and cancer (Scheller et al , ; Mihara et al , ; Jones & Jenkins, ). Here, IL‐6‐mediated homeostatic processes are facilitated by classic signaling, while the disease‐associated functions of IL‐6 primarily (or even exclusively) reside with trans‐signaling (Hunter & Jones, ; Jones & Jenkins, ).…”

“…The rationale to target trans‐signaling in disease, rather than the “classic” IL‐6 signaling mode which is dependent on the membrane‐bound IL‐6R, is based on the opposing roles of IL‐6 in either maintaining homeostatic processes (e.g., regulation of B‐cell function, the acute phase response, and hematopoiesis), or conversely, driving chronic disease states such as inflammation and cancer (Scheller et al , ; Mihara et al , ; Jones & Jenkins, ). Here, IL‐6‐mediated homeostatic processes are facilitated by classic signaling, while the disease‐associated functions of IL‐6 primarily (or even exclusively) reside with trans‐signaling (Hunter & Jones, ; Jones & Jenkins, ). Notably, the experimental mouse IL‐6R antibodies (1F7 and 25F10) used in our current study block IL‐6 trans‐signaling in the mouse, and have previously been reported to ameliorate tumorigenesis in the Kras G12D LAC model, albeit not as effectively as the robust anti‐tumor activity observed here with A17pro (Brooks et al , ).…”

“…Notably, the experimental mouse IL‐6R antibodies (1F7 and 25F10) used in our current study block IL‐6 trans‐signaling in the mouse, and have previously been reported to ameliorate tumorigenesis in the Kras G12D LAC model, albeit not as effectively as the robust anti‐tumor activity observed here with A17pro (Brooks et al , ). In addition, existing anti‐IL‐6R antibody therapies used in the clinic (and for that matter, also those against IL‐6), such as tocilizumab and sarilumab, block both protective (i.e., classic) and pathological (i.e., trans) signaling activities of IL‐6, causing side effects such as compromised host defense against bacteria (i.e., infections), imbalanced metabolism leading to higher blood cholesterol and triglyceride levels, and increased risk of gastrointestinal tract perforations (Rose‐John et al , ; Jones & Jenkins, ). Therefore, highly selective and potent ADAM17 inhibitors such as A17pro used in our current study, which specifically block pathological mouse/human trans‐signaling, promise to be more effective in suppressing disease states, including LAC, associated with IL‐6 trans‐signaling, and with less adverse effects.…”

Oncostatin M expression in the mouse uterus during early pregnancy promotes embryo implantation and decidualization

“…IL-6 family consists of IL-6, IL-11, IL-27, IL-31, OSM, leukemia inhibitory factor (LIF), ciliary neurotrophic factor, cardiotrophin 1 and cardiotrophin-like cytokine factor 1 [4]. IL-6 family consists of IL-6, IL-11, IL-27, IL-31, OSM, leukemia inhibitory factor (LIF), ciliary neurotrophic factor, cardiotrophin 1 and cardiotrophin-like cytokine factor 1 [4].…”