Role of IL-17 in the Th1 systemic defects in rheumatoid arthritis through selective IL-12Rbeta2 inhibition.
BACKGROUND
Patients with rheumatoid arthritis (RA) have a systemic Th1 defect associated with inflammation.


OBJECTIVE
To examine the hypothesis that interleukin 17 (IL-17) contributes to this defect.


METHODS
IL-17 effects on Th1 markers were examined on T-bet and interferon gamma (IFNgamma) expression in peripheral blood mononuclear cells (PBMCs) from patients with RA or healthy controls (HC). Receptor specificities were determined by analysis of the Th1-specific IL-12 receptor beta2 (IL-12Rbeta2), Th17-specific IL-23R and the common IL-12Rbeta1 chain expression. Effects of IL-17 or IFNgamma on IL-6, IL-1, IL-8, matrix metalloproteinase-8 (MMP-8) were measured by real-time RT-PCR in RA synovial cells.


RESULTS
RA PBMCs were less responsive to IL-12-induced IFNgamma than HC PBMCs. IL-12 hyporesponsiveness was increased by IL-17 treatment associated with a selective reduction in IL-12Rbeta2, but not IL-23R, IL-12Rbeta1 or T-bet, which was reversed with IL-17R inhibition. IL-17 inhibited IL-12Rbeta2 expression in developing Th1 cells. In RA synovial cells, IL-17 induced IL-6, IL-1, IL-8 and MMP-8, whereas IFNgamma had minimal or inhibitory effects.


CONCLUSIONS
In RA, IL-12 hyporesponsiveness is associated with IL-17R-mediated downregulation of IL-12Rbeta2 expression. IL-17 may reinforce Th17 lineage commitment and proinflammatory and destructive effects through Th1 inhibition and positive feedback effects in RA synovial cells. Anti-inflammatory effects of IL-17/IL-17R antagonism may include the restoration of protective Th1 responses.
Toh
Myew-Ling
ML
Department of Immunology and Rheumatology, Immunogenomics and Inflammation Research Unit EA 4130, University of Lyon, Edouard Herriot Hospital, Lyon, France.
Kawashima
Masanori
M
Hot
Arnaud
A
Miossec
Philippe
P
Miossec
Pierre
P
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D020381:Interleukin-17 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D053707:Receptors, Interleukin-12 / Q000037:antagonists & inhibitors* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013583:Synovial Membrane / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology*; D000098815:T-bet Transcription Factor
C508439:IL12RB2 protein, human; D020381:Interleukin-17; D012333:RNA, Messenger; D053707:Receptors, Interleukin-12; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma