Inflammatory and mitogenic signals drive interleukin 23 subunit alpha (IL23A) secretion independent of IL12B in intestinal epithelial cells

Abstract

The heterodimeric cytokine interleukin-23 (IL-23 or IL23A/IL12B) is produced by dendritic cells and macrophages and promotes the proinflammatory and regenerative activities of T helper 17 (Th17) and innate lymphoid cells. A recent study has reported that IL-23 is also secreted by lung adenoma cells and generates an inflammatory and immune-suppressed stroma. Here, we observed that proinflammatory tumor necrosis factor (TNF)/NF-κB and mitogen-activated protein kinase (MAPK) signaling strongly induce IL23A expression in intestinal epithelial cells. Moreover, we identified a strong crosstalk between the NF-κB and MAPK/ERK kinase (MEK) pathways, involving the formation of a transcriptional enhancer complex consisting of proto-oncogene c-Jun (c-Jun), RELA proto-oncogene NF-κB subunit (RelA), RUNX family transcription factor 1 (RUNX1), and RUNX3. Collectively, these proteins induced IL23A secretion, confirmed by immunoprecipitation of endogenous IL23A from activated human colorectal cancer (CRC) cell culture supernatants. Interestingly, IL23A was likely secreted in a noncanonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely because IL12B expression is absent in CRC cells. Given recent evidence that IL23A promotes tumor formation, we evaluated the efficacy of MAPK/NF-κB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11–7082 (an IKKα/IκB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600E mutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a noncanonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.

Lack of evidence for expression and function of IL-39 in human immune cells

“…However, recent papers underscore the possibility that the IL-23A-p19 subunit can be secreted as a standalone protein as shown that activated neutrophils and monocytes not only secrete the IL-23 p19/p40 heterodimer in cell supernatants, but also the IL-23A-p19 subunit which was not complexed with EBI3 [ 20 ]. In addition, a recent publication described that epthelial cancer cells could secrete the p19 subunit without being complexed to p40 beta subunit [ 21 ]. A similar situation may be applicable in our cellular system, especially under conditions where the cells highly overexpress the p19 protein after transfection.…”

Role of NKG2a/c+CD8+ T cells in pathogenic versus non-pathogenic SIV infections

“…We therefore measured IL-23, IP-10 (CXCL10), and Hsp60. We chose IL-23 because the transcriptomic analysis revealed that NKG2 a/c + CD8 + T cells expressed high levels of IL23R and because this pro-inflammatory cytokine is known to be expressed in the gut ( Lim et al., 2020 ). IP-10 was selected because it was shown that it is increased in the gut during SIVmac infection ( Ploquin et al., 2016 ).…”

Shiga toxin remodels the intestinal epithelial transcriptional response to Enterohemorrhagic Escherichia coli

“…Typically, the two subunits are expressed together and form the IL23 heterodimer (84), but the gene expression of these two subunits is not always temporally synchronized (85). It is possible that IL23 p19 could have an independent function or an alternative partner in intestinal epithelial cells, as has been suggested recently (86). In contrast to the induction of IL23A, Stx appears to inhibit expression of IFNG and many ISGs such as CXCL11, since these cytokines and downstream factors were downregulated in WT compared to ∆∆stx infected colons.…”