Different roles of interleukin 6 and interleukin 11 in the liver: implications for therapy

Abstract

The interleukin 6 (IL6) family of proteins regulate important cellular processes and act through a variety of signaling pathways via a shared gp130 receptor. In the liver, there is a large body of evidence showing a protective and pro-regenerative role for IL6 cis and trans signaling. While a few studies suggest a pathological role for IL6 trans-signaling in the liver. IL11 is often thought of as similar to IL6 and redundancy has been inferred. However, recent studies reveal that IL6R and IL11RA are expressed on dissimilar cell types and these cytokines actually have very different roles in biology and pathology. In the liver, IL6R is mostly expressed on immune cells, whereas IL11RA is highly expressed on hepatocytes and hepatic stellate cells, both of which exhibit autocrine IL11 activity. In contrast to the beneficial effects of IL6 in the liver, IL11 causes liver disease and its expression in stromal and parenchymal cells leads to fibrosis, inflammation, steatosis and hepatic failure. In this review, we address IL6 and IL11 in the context of liver function. We end by discussing the possibility of IL6 gain-of-function versus IL11 inhibition as therapeutic approaches to treat liver disease. ^1,2.

Keywords: IL-11; IL-6; NASH; fibrosis; gp130; regeneration; steatosis.

Figure 1.

Number of publications for IL6 (gray) or IL11 (black) by year (1985–2019). The R package Pubmedwordcloud was used to generate these plots using case insensitive keywords ‘il6ʹ, ‘il-6ʹ, ‘interleukin-6ʹ, ‘interleukin 6ʹ for IL6 and ‘il-11ʹ, ‘interleukin-11ʹ and ‘interleukin 11ʹ for IL11

Figure 2.

IL11RA is expressed on different cell types as compared to IL6R. Graphs showing example data for (a) correlated gene expression (COL1A1 vs COL1A2), (b) unrelated gene expression (COL1A1 vs GAPDH), and (c) IL11RA vs IL6R gene expression, which appears largely exclusive and in disparate cell types. The expression values are normalized counts obtained from the FANTOM consortium.