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

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-kappaB and mitogen-activated protein kinase (MAPK) signaling strongly induces IL23A expression in intestinal epithelial cells. Moreover, we identified a strong cross-talk between the NF-kappaB 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-kappaB 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 non-canonical form, as it was not detected by an ELISA specific for heterodimeric IL-23 likely becauseIL12B expression is absent in CRC cells. Given recent evidence that IL23Apromotes tumor formation, we evaluated the efficacy of MAPK/NF-kappaB inhibitors in attenuating IL23A expression and found that the MEK inhibitor trametinib and BAY 11-7082 (an IKKalpha/IkappaB inhibitor) effectively inhibited IL23A in a subset of human CRC lines with mutant KRAS or BRAFV600Emutations. Together, these results indicate that proinflammatory and mitogenic signals dynamically regulate IL23A in epithelial cells. They further reveal its secretion in a non-canonical form independent of IL12B and that small-molecule inhibitors can attenuate IL23A secretion.