The Immunobiology of the Interleukin-12 Family: Room for Discovery

Abstract

The discovery of interleukin (IL)-6 and its receptor subunits provided a foundation to understand the biology of a group of related cytokines: IL-12, IL-23, and IL-27. These family members utilize shared receptors and cytokine subunits and influence the outcome of cancer, infection, and inflammatory diseases. Consequently, many facets of their biology are being therapeutically targeted. Here, we review the landmark discoveries in this field, the combinatorial biology inherent to this family, and how patient datasets have underscored the critical role of these pathways in human disease. We present significant knowledge gaps, including how similar signals from these cytokines can mediate distinct outcomes, and discuss how a better understanding of the biology of the IL-12 family provides new therapeutic opportunities.

Figure 1.. The interleukin-6/12 family of cytokines and their receptors.

IL-6 is a monomeric cytokine that forms a symmetrical hexameric signaling complex with the IL-6Rα chain and gp130. Proteolytic processing of membrane bound IL-6Rα results in the generation of a soluble form of the receptor subunit (sIL-6Rα) that possesses the ability to signal in trans on cells that express gp130 but not IL-6Rα. IL-27 is a heterodimeric cytokine composed of the receptor-like subunit EBI3 (Epstein-Barr virus-induced molecule 3) and IL-27p28 (IL-30). IL-27 binds a heterodimeric receptor composed of gp130 and IL-27Rα (WSX-1 or TCCR). IL-12 is a heterodimeric cytokine consisting of the receptor-like component IL-12p40 and IL-12p35. IL-12 utilizes a heterodimeric receptor complex for signaling made up of IL-12Rβ1 and IL-12Rβ2. The IL-12 component p40 can also dimerize with IL-23p19 to form IL-23. The receptor for IL-23 consists of IL-12Rβ1 that is shared with IL-12 and a unique IL-23Rα chain. The relationship between these cytokines is illustrated by their shared usage of cytokine and receptor subunits and the homology within the structural domains of the cytokines and their receptors. Binding of these cytokines to their receptors results in the activation of JAK/STAT signaling pathways. The specific JAK and STAT proteins downstream of receptor binding are displayed. The STAT proteins attributed to the in vivo biological activity of these cytokines are bolded.

Figure 2.. Timeline of the discovery, functional characterization and development of therapeutics to limit the activity of IL-6, IL-12, IL-23 and IL-27.

Key events highlighting the discovery of (A) IL-6, (B) IL-12, IL-23 and (C) IL-27, their receptors, their biological function and the approval of therapeutics to treat diseases mediated by this family of cytokines over the past 41 years.

Figure 3.. Effect of IL-6/12 cytokines on T cell activities.

(A) Production of IL-6 by dendritic cells, as well as other innate cells, supports the differentiation of CD4⁺ T cells into T follicular helper (Tfh) cells by promoting the expression of CXCR5, IL-21 and Bcl6. Tfh cells subsequently provide signals to B cells through CD40-CD40L interactions that induce B cell proliferation and their differentiation into antibody-secreting cells. (B) Production of IL-6 by dendritic cells can inhibit the ability of TGF-β to upregulate Foxp3 expression in CD4+ T cells, preventing their development into regulatory T cells and instead favoring their development into Th17 cells in response to RORγt expression. These host protective Th17 cells promote mucosal defense, barrier tissue integrity and promote neutrophil recruitment. Exposure of Th17 cells to dendritic cell-derived IL-23 favors their maturation into pathogenic Th17 cells that express IL-17, IFN-γ and GM-CSF and promote chronic tissue inflammation. IL-27 functions to antagonize the differentiation of CD4⁺ T cells into Th17 cells. (C) IL-12 secretion by dendritic cells supports the upregulation of Tbet in CD4⁺ and CD8⁺ T cells thereby promoting their differentiation into Th1 cells. IL-27 supports the expansion of CD8⁺ T cells and their production of IFN-γ. IL-12 and IL-27 can also induce the development of Tr1 (Type 1 regulatory) cells that are characterized by their ability to co-express IL-10 and IFN-γ. Tr1 cells function to limit inflammatory T cell responses.

Figure 4.. Therapeutic targeting of IL-6, IL-12 and IL-23.

(A) Various drugs that block IL-6, IL-6R or cell signaling in response to IL-6 that are in pre-clinical testing, clinical trials or part of routine use in the clinic. The signaling blockers are JAK inhibitors. (B) Various drugs that are clinically approved to block the activity of IL-12 and IL-23 (p40 inhibitors) or specifically target IL-23 (p19 inhibitors). These cytokine inhibitors are utilized to treat certain autoimmune and inflammatory conditions in humans.