IL-23 and IL-12 responses in activated human T cells retrovirally transduced with IL-23 receptor variants.
Interleukin-23 (IL-23) is a regulator of cellular immune responses involved in controlling infections and autoimmune diseases. Effects of IL-23 on T cells are mediated via a receptor complex consisting of an IL-12Rbeta1 and a specific IL-23R chain. The R381Q and P310L variants of the IL-23R were recently reported to be associated with autoimmune diseases, suggesting they have an effect on IL-23R function. To investigate this matter, these variants and a newly identified variant, Y173H, were retrovirally transduced into human T cell blasts and functionally characterized by measuring the IL-23-induced signal transduction pathway (i.e., STAT1, STAT3 and STAT4 phosphorylation), and IFN-gamma and IL-10 production. No differences were detected between the genetic variants and wild-type in the function of the IL-23R-chain. Furthermore, while comparing IFN-gamma and IL-10 production in response to IL-23 and IL-12, we found IL-23 to be a more potent IL-10 inducer, and IL-12 a more potent IFN-gamma inducer. In addition, IL-23 also exerted a minor IL-12-like effect by inducing IL-23R-independent, IL-12Rbeta1-dependent STAT4 phosphorylation and IFN-gamma production. In conclusion, the reported association between R381Q and P310L variants of the IL-23R and autoimmune diseases does not depend on differences in functional activity between wild-type and R381Q and P310L variants of the IL-23R.
de Paus
Roelof A
RA
Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
van de Wetering
Diederik
D
van Dissel
Jaap T
JT
van de Vosse
Esther
E
D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000502:physiology*; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D010766:Phosphorylation; D019154:Protein Splicing; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000502:physiology; D012190:Retroviridae / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
C508609:IL10 protein, human; C508439:IL12RB2 protein, human; C515500:IL23R protein, human; D053759:Interleukin-23; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma