Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
p53 Regulates Th17-Mediated Autoimmune Arthritis.
Park1, Jin-Sil, Cho1, Mi-La, Lim1, Mi-Ae, Moon1, Young-Mee, Oh1, Hye-Jwa, Jhun1, Joo-Yeon, Ryu1, Jun-Geol
A great deal of effort has focused on the role of the p53 tumor suppressor in cancer. Recently, previous observations indicated that p53 can play a protective role in several immune and inflammatory diseases. To identify the role of p53 in autoimmune disorders, we examined whether p53 could regulate the in vivo effects of rheumatoid arthritis (RA).
Arthritis severity of wild type or p53 knockout (KO) mice with CIA was assessed by clinical and histologic scoring. p53 agonist or antagonist was administered via intraperitoneal injection in C57BL/6 mice and the in vivo effects were determined by assessing joint swelling, histological changes. The proliferation was determined by [3H] thymidine incorporation and concentrations of CII-specific IgG2a, IL-17, and TNF-a were determined by ELISA. The expression of Th17 and Treg cells was analyzed by flow cytometry. Adoptive transfer of CD4+ T cells from WT or p53KO mice, respectively, to IL-17KO mice was performed. In human, CD4+ T cells from human peripheral blood mononuclear cells were differentiated into Th17 cells with p53 agonist and proportion of Th17/Treg was determined by flow cytometry.
p53 inhibits Th17 differentiation of CD4+ T cells, while p53 promotes expression of Foxp3 in vitro. We observed that p53 mediated the suppression of Th17 differentiation by physically interacting with STAT3 or STAT5, which is major transcription factor for Th17 and Treg, respectively. p53 deficiency in mice exacerbated disease in collagen-induced arthritis (CIA) model, whereas p53 activation ameliorated the severity of arthritis through regulation of the balance between Th17 and Treg cells. Adoptive transfers of CD4+ T cells from p53 KO mice with CIA into IL-17 KO with CIA, which is resistant to CIA, induced severe autoimmune arthritis. p53 could regulate the differentiation of Th17 more effectively in patients with RA, when compare to healthy controls.
These results demonstrated that p53 serves as a novel regulator of Th17-Treg mediated autoimmunity and could be a new therapeutic target for rheumatoid arthritis.
This research was supported by Publinc welfare&Safety research program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (20100020767)
To cite this abstract, please use the following information:
Park, Jin-Sil, Cho, Mi-La, Lim, Mi-Ae, Moon, Young-Mee, Oh, Hye-Jwa, Jhun, Joo-Yeon, et al; p53 Regulates Th17-Mediated Autoimmune Arthritis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :850