Abstract
Interleukin (IL)-30, the IL-27p28 subunit of the heterodimeric cytokine IL-27, acts as an antagonist of IL-27 and IL-6 signaling in murine cells via glycoprotein 130 (gp130) receptor and additional binding partners. Thus far, functions of IL-30 have not been fully elucidated in human cells. We demonstrate that like IL-27, IL-30 upregulated TLR4 expression to enhance lipopolysaccharide-induced TNF-α production in human monocytes; however, these IL-30-mediated activities did not reach the same levels of cytokine induction compared to IL-27. Interestingly, IL-30- and IL-27-mediated interferon-γ-induced protein 10 (IP-10) production required WSX-1 engagement and signal transducer and activator of transcription (STAT) 3 phosphorylation; furthermore, IL-30 induced STAT phosphorylation after 16 h, whereas IL-27 induced STAT phosphorylation within 30 min. This prompted us to examine if a secondary mediator was required for IL-30-induced pro-inflammatory functions, and hence we examined IL-6-related molecules. Combined with inhibition of soluble IL-6 receptor α (sIL-6Rα) and data showing that IL-6 inhibited IL-30/IL-27-induced IP-10 expression, we demonstrate a role for sIL-6Rα and gp130 in IL-30-mediated activity in human cells.
Highlights
Interleukin (IL)-27, discovered by Pflanz et al, is composed of non-covalently associated IL-27p28 helical subunit with Epstein–Barr virus (EBV)-induced gene 3 (EBI3)-soluble receptor subunit [1]
To model IL-27 and IL-27 p28 subunit (IL-30) functions, we focused on human monocytic cells using the THP-1 cell line and primary monocytes as model systems
We previously reported that IL-27 mediates pro-inflammatory cytokine and chemokine production in human monocytes, including interferon-γinduced protein 10 (IP-10), we decided to use this chemokine as a readout for dose–response analysis [8]
Summary
Interleukin (IL)-27, discovered by Pflanz et al, is composed of non-covalently associated IL-27p28 helical subunit with Epstein–Barr virus (EBV)-induced gene 3 (EBI3)-soluble receptor subunit [1]. This heterodimeric cytokine is produced by activated antigen-presenting cells such as monocytes, macrophages, and dendritic cells (DCs) [1, 2]. IL-27 signals through the heterodimeric receptor subunits WSX-1 (IL-27 receptor α/T cell cytokine receptor) and glycoprotein 130 (gp130) to induce activation of signal transducer and activator of transcription (STAT) 1 and STAT3 in monocytic cells [2, 8]. WSX-1 and gp130 are found co-expressed on monocytes, macrophages, DCs, T and B lymphocytes, natural killer cells, mast cells, and endothelial cells [2, 9, 10], allowing these cells to respond to IL-27 and possibly IL-30
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