AT-rich-interactive domain-containing protein 5A functions as a negative regulator of retinoic acid receptor-related orphan nuclear receptor γt-induced Th17 cell differentiation.
OBJECTIVE
The proinflammatory cytokines tumor necrosis factor α and interleukin-6 (IL-6) and the Th17 cell cytokine IL-17A are implicated in the pathogenesis of rheumatoid arthritis (RA), and the blockade of these cytokines by biologic agents provides clinical benefits for RA patients. We undertook this study to clarify the mechanisms underlying the efficacy of IL-6 blockade in RA and to find a novel target for treatment of RA.


METHODS
We examined gene expression profiles of CD4+ T cells by DNA microarray analysis before and after treatment with an anti-IL-6 receptor antibody, tocilizumab (TCZ), in RA patients who exhibited good clinical responses to the treatment. Using murine CD4+ T cells, we then examined the roles of a newly identified molecule whose expression was significantly reduced in CD4+ T cells by TCZ therapy. We also examined the effect of the forced expression of the molecule on retinoic acid receptor-related orphan nuclear receptor γt (RORγt)-induced IL-17A production in CD4+ T cells and on RORγt-induced IL-17A promoter activation.


RESULTS
We identified AT-rich-interactive domain- containing protein 5A (ARID-5A) as a new molecule down-regulated by IL-6 blockade in the form of TCZ therapy. IL-6 induced the expression of ARID-5A in CD4+ T cells during Th17 cell differentiation by a STAT-3-dependent mechanism, whereas IL-6-induced ARID-5A expression was not affected by the absence of RORγt, a lineage-specifying transcription factor of Th17 cells. Furthermore, ARID-5A physically associated with RORγt through its N-terminal region and inhibited RORγt-induced Th17 cell differentiation.


CONCLUSIONS
ARID-5A is a lineage-specific attenuator of Th17 cell differentiation and may be involved in the pathogenesis of RA.
Chiba University, Chiba, Japan.
Yukari
Y
Saito
Shin-Ichiro
S
Kagami
Yoshie
Y
Sanayama
Kei
K
Ikeda
Akira
A
Suto
Daisuke
D
Kashiwakuma
Shunsuke
S
Furuta
Itsuo
I
Iwamoto
Ken
K
Nonaka
Osamu
O
Ohara
Hiroshi
H
Nakajima
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D006801:Humans; D019410:Interleukin-16 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000276:immunology; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D058504:Th17 Cells / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism*
C000590740:ARID5A protein, human; D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D004268:DNA-Binding Proteins; D019410:Interleukin-16; D020381:Interleukin-17; D009687:Nuclear Proteins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D019947:Receptors, Interleukin-6; D018168:Receptors, Retinoic Acid; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; C502936:tocilizumab