A naturally occurring, soluble antagonist of human IL-23 inhibits the development and in vitro function of human Th17 cells

• Published in: The Journal of immunology (1950) 2010-12, Vol.185 (12), p.7302-7308
• Main Authors: Yu, Raymond Y, Gallagher, Grant
• Format: Article
• Language: English
• Subjects: Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Line; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Exons - genetics; Exons - immunology; Humans; Interleukin-23 - antagonists & inhibitors; Interleukin-23 - genetics; Interleukin-23 - immunology; Interleukin-23 - metabolism; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Phosphorylation - genetics; Phosphorylation - immunology; Protein Biosynthesis - genetics; Protein Biosynthesis - immunology; Protein Structure, Tertiary; Receptors, Interleukin - biosynthesis; Receptors, Interleukin - genetics; Receptors, Interleukin - immunology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Messenger - immunology; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - immunology; STAT3 Transcription Factor - metabolism; Th17 Cells - cytology; Th17 Cells - immunology; Th17 Cells - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1002410

Th17 CD4 cells are critical to inflammation. Their secretion of IL-17 drives inflammation in human diseases, including inflammatory bowel disease. Differentiation of mature Th17 cells depends on stimulation with IL-6, TGF-β, and IL-21 and the induction of RORγt, but IL-23 is essential to Th17 phenotype, stability, and function. Induction of Th17 cells can be antagonized by IL-4 or IFN-γ, but mechanisms through which terminal differentiation can be inhibited have not been identified. Human IL-23Rα (HuIL23Rα)-chain mRNA transcripts exist that lack exon 9 ("Δ9"); these are translated to a truncated receptor containing the entire external domain. This soluble variant of the HuIL23Rα-chain antagonizes Th17 maturation. It is secreted and present at low levels in the blood. It represents 10% of HuIL23Rα-chain mRNA, binds IL-23 in solution, and inhibits the phosphorylation of STAT3 caused by IL-23. In in vitro Th17 cell differentiation experiments, Δ9 inhibits the production of the Th17-associated cytokines IL-17A and IL-17F. Δ9 does not bind IL-12; thus, it is a specific inhibitor of IL-23 and a modulator of Th17 cells. Our results indicate that this soluble form of HuIL23Rα likely functions to regulate Th17 activity.