NF-AT5 is a critical regulator of inflammatory arthritis

Abstract

Objective To investigate the role of nuclear factor of activated T cells 5 (NFAT5), which is known as an osmoprotective transcription factor, in synovial hyperplasia and angiogenesis in rheumatoid arthritis (RA) Methods Expression of NFAT5 was examined in the synovial tissues and synoviocytes of RA patients using immunohistochemistry and Western blot analysis, respectively. The mRNAs of RA synoviocytes and human umbilical vein endothelial cells (HUVEC) transfected with dummy siRNA or NFAT5 siRNA were profiled using microarray technology. Assays to determine synoviocyte apoptosis and proliferation were performed in the presence of NFAT5 siRNA.VEGF165-induced angiogenesis was assessed by measuring the proliferation, tube formation, and wounding migration of HUVEC. Experimental arthritis was induced in mice by injection of anti-type II collagen antibody. Results NFAT5 was highly expressed in the rheumatoid synovium and its activity was increased by proinflammatory cytokines, such as IL-1β and TNF-α. The mRNA profiling of synoviocytes and HUVEC transfected with NFAT5-targeted siRNA revealed three major changes in cellular processes associated with the pathogenesis of RA: cell cycle and survival, angiogenesis, and cell migration. Consistent with these results, NFAT5 knock-down in RA synoviocytes and HUVEC inhibited their proliferation/survival and impeded angiogenic processes in HUVEC. Mice with NFAT5 haplo-insufficiency (NFAT5+/-) developed very limited degree of synovial proliferation in histological analysis, decreased angiogenesis, and exhibited a nearly complete suppression of experimentally induced arthritis. Conclusion NFAT5 regulates synovial proliferation and angiogenesis in chronic arthritis.

Tonicity-responsive enhancer binding protein haplodeficiency attenuates seizure severity and NF-κB-mediated neuroinflammation in kainic acid-induced seizures

“…Recent reports have shown that TonEBP haploinsufficiency reduced inflammatory responses and alleviated pathology of chronic diseases, including rheumatoid arthritis and atherosclerosis. 25,26 Increased TonEBP expression was observed in rheumatoid synovium, where TonEBP haploinsufficiency reduced the cytokine-induced proliferation and angiogenesis. 26 TonEBP in bone marrow-derived cells was required for atherosclerotic lesion formation and macrophage migration.…”

“…25,26 Increased TonEBP expression was observed in rheumatoid synovium, where TonEBP haploinsufficiency reduced the cytokine-induced proliferation and angiogenesis. 26 TonEBP in bone marrow-derived cells was required for atherosclerotic lesion formation and macrophage migration. TonEBP haploinsufficiency led to a significant reduction of aortic lesions in in vivo model of atherosclerosis.…”

NFAT5 Has a Job in the Brain

“…In several pathologic conditions, NFAT5 exacerbated the formation of damage regions. A lack of NFAT5 retarded the pathogenesis of atherosclerosis by declining the accumulation of MΦs in atherosclerotic lesions [54], and reduced the severity of arthritis with impaired inflammatory cell infiltration by inhibiting the secretion of C-C motif ligand 2 (CCL2) [50], joint destruction, and synovial hyperplasia [55]. NFAT5 also affected cancer proliferation and metastasis by enhancing protumor MΦ2 differentiation [56].…”

Role of NFAT5 in Osteogenic Differentiation of Human Adipose Tissue-Derived Mesenchymal Stem Cells

“…주로 신장 등의 높은 삼투압 환경에서 세포를 보호 하며 여러 기관에서 세포의 생존, 발달 등에 관련된 기능을 한다 [3,18]. 특히 NFAT5는 세포질의 삼투질 농도에 의해 발현 이 조절되며 활막세포와 혈관내피세포의 증식과 분화에 중요 한 역할을 하는 조절인자라고 보고 되어져 있고 [9,30] (Fig. 1A, B 제 시킨 세포에 TNF-α를 처리했을 때에는 TNF-α에 의한 지방 분화 억제효과가 영향을 받지 않았다 (Fig.…”