AB0145 THE INHIBITION OF JAK PATHWAY WAS ASSOCIATED WITH REDUCTION OF AUTOPHAGY IN SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS PATIENTS
2019
Background: The pathway of Janus tyrosine kinases (JAKs) has a central role in the pathogenesis of rheumatoid arthritis (RA) by regulating multiple immune functions and cytokine production. The orally available JAK inhibitor CP-690,550, named tofacitinib, is able to inhibit Jak1, Jak2 and Jak3 and it showed a great clinical efficacy in RA patients not responding to methotrexate or TNF-inhibitors (1). Autophagy, a highly conserved mechanism involved in the degradation of intracellular components, was found to be dysregulated in several autoimmune diseases including RA (2). In fact, fibroblasts like synoviocytes (FLS) from RA patients showed a resistance to apoptosis associated with the induction of autophagy (3). Maeshima and colleagues recently demonstrated that tofacitinib suppressed proliferation, but not apoptosis, of CD4+ T cells derived from the synovium (4), but to date there are no data on the effect of inhibition of JAK pathway on autophagy. Objectives: Since hyperactive autophagy has been associated with impaired apoptosis of RA FLS, the aim of the study was to investigate the role of tofacitinib in modulating autophagy and apoptosis in FLS from RA patients. Methods: Primary RA FLS isolated from RA biopsies (Figure 1A) were cultured in presence of autophagy inducer rapamycin (as control condition) and tofacitinib (1μM). After 24h of culture, autophagy was evaluated both by flow cytometry and western blot analysis. Apoptosis was analyzing by annexin V (AV) and propidium iodide (PI) apoptosis detection kit by flow cytometry. Results: As expected tofacitinib inhibited the expression of the phosphorylated form of STAT3 (p Conclusion: The results of this study elucidated a new mechanism of action of tofacitinib related to autophagy modulation and led to a better understanding of the role of autophagy in RA. This study was supported by an unconditioned Research grant from Pfizer Inc. References [1] Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet2013; 381: 451-60. [2] Vomero M, Barbati C, Colasanti T, et al. Autophagy and Rheumatoid Arthritis: Current Knowledges and Future Perspectives. Front Immunol. 2018;9:1577. [3] Shin YJ, Han SH, Kim DS, et al. Autophagy induction and CHOP under-expression promotes survival of fibroblasts from rheumatoid arthritis patients under endoplasmic reticulum stress. Arthritis Res Ther. 2010; 12:R19. [4] Maeshima K, Yamaoka K, Kubo S, et al. The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-γ and interleukin-17 production by human CD4+ T cells. Arthritis Rheum. 2012;64:1790-8. Disclosure of Interests: Marta Vomero: None declared, Mattia Caliste : None declared, cristiana barbati: None declared, Tania Colasanti: None declared, francesca spinelli: None declared, Fulvia Ceccarelli: None declared, Carlo Perricone Speakers bureau: BMS; Lilly, Celgene, Sanofi, Annacarla Finucci: None declared, Mariangela Speziali: None declared, Alessandra Ida Celia: None declared, Michele Bombardieri Grant/research support from: Celgene, Consultant for: Medimmune, fabrizio conti: None declared, Guido Valesini: None declared, cristiano alessandri: None declared
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