Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
The Critical Role of STAT3 in the Th17 Differentiation of RA Synovial T Cells.
Ju, Ji Hyeon, Cho, Mi-La, Kim, Ji Min, Jeong, Yong-Geun, Kwok, Seung-Ki, Su Park, Kyung, Park, Sung-Hwan
STAT3, a signal transduction molecule of inflammatory cytokines such as IL-6, IL-21 and IL-23, plays an important role during the differentiation of CD4+ T cell into Th17 cells (Th17). Since Th17 is the pathogenic cell in autoimmune arthritis, STAT3 has also been suspected to be closely involved in the pathophysiology. This study aims to investigate the mechanism of rheumatoid arthritis (RA) related to the differentiation of Th17 and to identify the role of STAT3.
Cytokine levels in the peripheral blood and synovial fluid of RA patients were measured with ELISA. Immunohistochemical staining of RA synovium was performed to investigate the relationship between synovitis and the expression of STAT3. CD4+ T cells, isolated from peripheral blood and synovial fluid of normal individuals and RA patients, were respectively stimulated with factors leading to Th17 differentiation (anti-CD3 1 mg/ml, anti-CD28 1 mg/ml, IL-23 5 ng/ml, TGF-b 2 ng/ml, IL-6 10 ng/ml, anti-IFN-g 10 mg/ml, anti-IL-4 mg/ml) or regulatory T cells (Treg) differentiation (anti-CD3 1 mg/ml, anti-CD28 1 mg/ml, TGF-b 20 ng/ml, IL-2 5 ng/ml), as known. STAT3 siRNA was transfected to CD4+ T cells during the differentiation of Th17 cells, which was followed by FACS, RT-PCR and ELISA analyses in order to investigate the impact of STAT3 in Th17 and Treg differentiation.
IL-6, a Th17 related cytokine, was significantly increased in RA synovium (P<0.01). The number of Th17 cells in the synovial tissue was significantly higher in RA patients than in normal population. STAT3 and p727S-STAT3 expressions were significantly increased in RA synovium, and their expressions were positively related to the severity of synovitis such as infiltration of inflammatory cells and synovial proliferation (r=0.68, P<0.05). When STAT3 siRNA was transfected to the CD4+ T cell differentiation in normal individuals, IL-17 and IL-22 expressions and Th17 population decreased, whereas TGF-b expressions and Treg population increased (P<0.05). In contrast to the STAT3 inhibition, when STAT5, the transcription factor for Treg, was inhibited, the number of Th17 was increased and that of Treg was decreased (P<0.05). Similar findings were observed in the CD4+ T cells isolated from peripheral blood of RA patients. Notably, T cells from RA synovial fluid were significantly decreased in differentiating into Th17 (RASF 0.2% < RAPB 0.5% < HCPB 0.7%, P<0.05) while increasing the proportion of Treg (RASF 20% > RAPB 10%, HCPB 11%, P<0.05).
The downstream signaling of STAT3 plays a critical role in CD4+ T cell differentiating into Th17 as well as Treg. Inhibition of STAT3 in CD4+ T cells of RA synovium effectively attenuated the differentiation of Th17. By simultaneously achieving Th17 inhibition and Treg stimulation, the regulation of STAT3 promises a novel strategy for RA treatment.
To cite this abstract, please use the following information:
Ju, Ji Hyeon, Cho, Mi-La, Kim, Ji Min, Jeong, Yong-Geun, Kwok, Seung-Ki, Su Park, Kyung, et al; The Critical Role of STAT3 in the Th17 Differentiation of RA Synovial T Cells. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :370