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.

• Authors: Kee Siang Lim, Zachary Wei Ern Yong, Huajing Wang, Tuan Zea Tan, Ruby Yun-Ju Huang, Daisuke Yamamoto, Noriyuki Inaki, Masaharu Hazawa, Richard W Wong, Hiroko Oshima, Masanobu Oshima, Yoshiaki Ito, Dominic Chih-Cheng Voon
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 19 Pg. 6387-6400 (05 08 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 32209656 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Lim et al.

Chemical References

• Core Binding Factor Alpha 2 Subunit
• Core Binding Factor Alpha 3 Subunit
• IL12B protein, human
• IL23A protein, human
• Interleukin-12 Subunit p40
• Interleukin-23 Subunit p19
• KRAS protein, human
• MAS1 protein, human
• Proto-Oncogene Mas
• RELA protein, human
• RUNX1 protein, human
• Runx3 protein, human
• Transcription Factor RelA
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins p21(ras)

Topics

• Amino Acid Substitution
• Colorectal Neoplasms (genetics, metabolism, pathology)
• Core Binding Factor Alpha 2 Subunit (genetics, metabolism)
• Core Binding Factor Alpha 3 Subunit (genetics, metabolism)
• Epithelial Cells (metabolism, pathology)
• HCT116 Cells
• Humans
• Inflammation (genetics, metabolism, pathology)
• Interleukin-12 Subunit p40 (genetics, metabolism)
• Interleukin-23 Subunit p19 (genetics, metabolism)
• Intestinal Mucosa (metabolism, pathology)
• MAP Kinase Signaling System
• Mutation, Missense
• Proto-Oncogene Mas
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Transcription Factor RelA (genetics, metabolism)