Details

Autor(en) / Beteiligte

• Park, Jin‐Sil
• Kwok, Seung‐Ki
• Lim, Mi‐Ae
• Kim, Eun‐Kyung
• Ryu, Jun‐Geol
• Kim, Sung‐Min
• Oh, Hye‐Joa
• Ju, Ji Hyeon
• Park, Sung‐Hwan
• Kim, Ho‐Youn
• Cho, Mi‐La

Titel

STA‐21, a Promising STAT‐3 Inhibitor That Reciprocally Regulates Th17 and Treg Cells, Inhibits Osteoclastogenesis in Mice and Humans and Alleviates Autoimmune Inflammation in an Experimental Model of Rheumatoid Arthritis

Ist Teil von

• Arthritis & rheumatology (Hoboken, N.J.), 2014-04, Vol.66 (4), p.918-929

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2014

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Objective To investigate the impact of STA‐21, a promising STAT‐3 inhibitor, on the development and progression of inflammatory arthritis and to determine the possible mechanisms by which STA‐21 has antiarthritic effects in interleukin‐1 receptor antagonist–knockout (IL‐1Ra–KO) mice, an animal model of rheumatoid arthritis (RA). Methods IL‐1Ra–KO mice were treated with intraperitoneal injections of STA‐21 (0.5 mg/kg) or vehicle 3 times per week for 3 weeks. The mouse joints were assessed for clinical and histologic features of inflammatory arthritis. CD4+CD25+FoxP3+ Treg cells and CD4+IL‐17+ cells were defined. Human peripheral blood mononuclear cell–derived monocytes or mouse bone marrow–derived monocyte/macrophage (BMM) cells were cultured in the presence of macrophage colony‐stimulating factor alone or together with RANKL and various concentrations of STA‐21, followed by staining of the cells for tartrate‐resistant acid phosphatase activity to determine osteoclast formation. Results STA‐21 suppressed inflammatory arthritis in IL‐1Ra–KO mice. The proportion of Th17 cells was decreased and the proportion of Treg cells expressing FoxP3 was markedly increased in the spleens of STA‐21–treated mice. Adoptive transfer of CD4+CD25+ T cells obtained from STA‐21–treated IL‐1Ra–KO mice markedly suppressed inflammatory arthritis. In vitro treatment with STA‐21 induced the expression of FoxP3 and repressed IL‐17 expression in both mouse and human CD4+ T cells. Moreover, STA‐21 prevented both mouse BMM cells and human monocytes from differentiating into osteoclasts in vitro. Conclusion STA‐21 improved the clinical course of arthritis in IL‐1Ra–KO mice. It increased not only the number of Treg cells but also the function of the Treg cells. It also suppressed Th17 cells and osteoclast formation. These data suggest that STA‐21 might be an effective treatment for patients with RA.