Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q.
Genome-wide association studies (GWAS) in several populations have demonstrated significant association of the IL23R gene with IBD (Crohn's disease (CD) and ulcerative colitis (UC)) and psoriasis, suggesting that perturbation of the IL-23 signaling pathway is relevant to the pathophysiology of these diseases. One particular variant, R381Q (rs11209026), confers strong protection against development of CD. We investigated the effects of this variant in primary T cells from healthy donors carrying IL23R(R381) and IL23R(Q381) haplotypes. Using a proprietary anti-IL23R antibody, ELISA, flow cytometry, phosphoflow and real-time RT-PCR methods, we examined IL23R expression and STAT3 phosphorylation and activation in response to IL-23. IL23R(Q381) was associated with reduced STAT3 phosphorylation upon stimulation with IL-23 and decreased number of IL-23 responsive T-cells. We also observed slightly reduced levels of proinflammatory cytokine secretion in IL23R(Q381) positive donors. Our study shows conclusively that IL23R(Q381) is a loss-of-function allele, further strengthening the implication from GWAS results that the IL-23 pathway is pathogenic in human disease. This data provides an explanation for the protective role of R381Q in CD and may lead to the development of improved therapeutics for autoimmune disorders like CD.
Department of Bioinformatics and Computational Biology, Genentech Inc, South San Francisco, California, United States of America. svetlana.pidasheva@gmail.com
Svetlana
S
Pidasheva
Sara
S
Trifari
Anne
A
Phillips
Jason A
JA
Hackney
Yan
Y
Ma
Ashley
A
Smith
Sue J
SJ
Sohn
Hergen
H
Spits
Randall D
RD
Little
Timothy W
TW
Behrens
Lee
L
Honigberg
Nico
N
Ghilardi
Hilary F
HF
Clark
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D002461:Cell Line, Transformed; D002999:Clone Cells; D017124:Conserved Sequence / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics*; D053759:Interleukin-23 / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018655:Lymphocyte Count; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018123:Receptors, Interleukin / Q000737:chemistry / Q000235:genetics*; D050791:STAT Transcription Factors / Q000378:metabolism; D013045:Species Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014019:Tissue Donors
C515500:IL23R protein, human; D053759:Interleukin-23; D018123:Receptors, Interleukin; D050791:STAT Transcription Factors; D001120:Arginine