title: A naturally occurring, soluble antagonist of human IL-23 inhibits the development and in vitro function of human Th17 cells.
abstract: 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.
authors.affiliation: Genetic Immunology Laboratory, Humigen, The Institute for Genetic Immunology, Hamilton, NJ 08690, USA.
authors.forename: Raymond Y
authors.initials: RY
authors.lastname: Yu
authors.forename: Grant
authors.initials: G
authors.lastname: Gallagher
mesh_terms: D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005091:Exons / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053759:Interleukin-23 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D014176:Protein Biosynthesis / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; C515500:IL23R protein, human; D053759:Interleukin-23; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012333:RNA, Messenger; C539900:RORC protein, human; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human