Historical overview of the interleukin-6 family cytokine

Abstract

Interleukin-6 (IL-6) has been identified as a 26-kD secreted protein that stimulates B cells to produce antibodies. Later, IL-6 was revealed to have various functions that overlap with other IL-6 family cytokines and use the common IL-6 signal transducer gp130. IL-6 stimulates cells through multiple pathways, using both membrane and soluble IL-6 receptors. As indicated by the expanding market for IL-6 inhibitors, it has become a primary therapeutic target among IL-6 family cytokines. Here, we revisit the discovery of IL-6; discuss insights regarding the roles of this family of cytokines; and highlight recent advances in our understanding of regulation of IL-6 expression.

Figure 1.

Receptor composition of IL-6 family cytokines. IL-6 family cytokines use gp130 to transduce their signals through gp130 homodimers or gp130-containing heterodimers. IL-6, IL-11, CNTF, CLCF1, and CLCF1/CLF require binding of their nonsignaling receptor to transduce signals. A new group of members (IL-27, IL-35, and IL-39) are heterodimeric cytokines: IL-27 consists of IL-27/p28 (IL-27α) and EBI3 (also known as IL-27β); in conformity to IL-12 containing IL-12p40 (IL-12α) and IL-12p35 (IL-12β), IL-23 (IL-23p19 [IL-23α] and IL-23p40 [IL-23β]), IL-35 (IL-23p40 and EBI3), and IL-39 (IL-23p19 and EBI3; Hunter, 2005; Ning-Wei, 2010; Wang et al., 2016a). These new members activate heterodimers of gp130. IL-6R exerts its biological effects via three different signaling modes. IL-6R expression is restricted to hepatocytes and several types of immune cells, whereas gp130 is ubiquitously expressed, reflecting the diverse roles of IL-6. In the classical mode of IL-6 signaling, the cytokine interacts with mIL-6R in cells that also express gp130 (Hunter and Jones, 2015). IL-6 also binds soluble IL-6R (sIL-6R), which is shed from cells following cleavage by ADAM metalloprotease 17 (ADAM17), and is also created by alternative mRNA splicing (Lust et al., 1992). The IL-6–sIL-6R complex binds to gp130, forming a dimer that initiates intracellular signaling, a process referred to as trans-signaling. Recently, a third mode of IL-6 signaling was identified: IL-6 trans-presentation (Heink et al., 2017). This mode is specific to dendritic cells, in which the IL-6–mIL-6R complex is presented to gp130 expressed on T cells to prime pathogenic Th17 cells. These alternative modes of IL-6 signaling contribute to multiple cellular processes.

Figure 2.

Spatiotemporal regulation of the IL-6 gene. Infections activate TLR and cytokine receptor signaling. NF-κB and NF-IL6 act primarily as TFs in IL-6 mRNA transcription. Moreover, some miRNAs target IL-6 mRNA to dampen its expression. IL-6 mRNA is posttranscriptionally regulated in macrophages. Engagement of TLR4 promotes IL-6 and Arid5a transcription through distinct pathways. Arid5a stabilizes IL-6 mRNA and counteracts Regnase-1 activity. Zcchc11 stabilizes IL-6mRNA by uridylation of miR-26. TRAM, TRIF-related adaptor molecule; CRM1, chromosomal region maintenance 1.