Bingtong Li1, Ping Li1, Liqi Bi2. 1. Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun, 130033, China. 2. Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun, 130033, China. biliqi66@126.com.
Abstract
INTRODUCTION: Anti-citrullinated protein antibodies (ACPAs) play an important role in rheumatoid arthritis (RA). Citrullinated proteins (CPs), which are produced by post-translational modification via peptidylarginine deiminase (PAD), are the target antigen of ACPAs and promote the generation thereof. Herein, we investigated whether iguratimod (IGU) affects the generation of CPs via PAD. METHODS: Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from three patients diagnosed with RA and treated with various concentrations of IGU, methotrexate (MTX), or dexamethasone (DXM) or without any drugs as a control for 8 h. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 in culture supernatants were tested by ELISA. CPs were measured by western blot, and the expression of PAD2 and PAD4 in cells was detected by qRT-PCR and western blot. RESULTS: PAD2 and PAD4 expressions in neutrophils but not in PBMCs were decreased by IGU at both the protein and mRNA levels (P < 0.05). CP expression in neutrophils but not in PBMCs was also inhibited by IGU. The inhibitory effect of IGU was dose-dependent. IGU, MTX, and DXM dose dependently decreased the secretion of TNF-α, IL-1β, IL-6, and IL-8 in neutrophils and PBMCs (P < 0.05); the inhibitory effect of IGU was not significantly different from that of MTX and DXM. CONCLUSIONS: IGU inhibited the expression of CPs by downregulating PADs in neutrophils from RA patients, and the effect was comparable to that of MTX and DXM at appropriate concentrations. These findings may provide guidance for more appropriate treatment of RA.Key Points• Iguratimod inhibited citrullinated protein expression in neutrophils from rheumatoid arthritis patients similarly to methotrexate and dexamethasone at appropriate concentrations.• The inhibitory effect was mediated by downregulation of peptidylarginine deiminases, providing insight into the mechanism of iguratimod as a treatment for rheumatoid arthritis.• This study may guide rheumatoid arthritis treatment and facilitate identification of other therapeutic targets.
INTRODUCTION: Anti-citrullinated protein antibodies (ACPAs) play an important role in rheumatoid arthritis (RA). Citrullinated proteins (CPs), which are produced by post-translational modification via peptidylarginine deiminase (PAD), are the target antigen of ACPAs and promote the generation thereof. Herein, we investigated whether iguratimod (IGU) affects the generation of CPs via PAD. METHODS: Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from three patients diagnosed with RA and treated with various concentrations of IGU, methotrexate (MTX), or dexamethasone (DXM) or without any drugs as a control for 8 h. The levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 in culture supernatants were tested by ELISA. CPs were measured by western blot, and the expression of PAD2 and PAD4 in cells was detected by qRT-PCR and western blot. RESULTS:PAD2 and PAD4 expressions in neutrophils but not in PBMCs were decreased by IGU at both the protein and mRNA levels (P < 0.05). CP expression in neutrophils but not in PBMCs was also inhibited by IGU. The inhibitory effect of IGU was dose-dependent. IGU, MTX, and DXM dose dependently decreased the secretion of TNF-α, IL-1β, IL-6, and IL-8 in neutrophils and PBMCs (P < 0.05); the inhibitory effect of IGU was not significantly different from that of MTX and DXM. CONCLUSIONS: IGU inhibited the expression of CPs by downregulating PADs in neutrophils from RApatients, and the effect was comparable to that of MTX and DXM at appropriate concentrations. These findings may provide guidance for more appropriate treatment of RA.Key Points• Iguratimod inhibited citrullinated protein expression in neutrophils from rheumatoid arthritispatients similarly to methotrexate and dexamethasone at appropriate concentrations.• The inhibitory effect was mediated by downregulation of peptidylarginine deiminases, providing insight into the mechanism of iguratimod as a treatment for rheumatoid arthritis.• This study may guide rheumatoid arthritis treatment and facilitate identification of other therapeutic targets.
Entities:
Keywords:
Anti-citrullinated protein antibody; Iguratimod; Peptidylarginine deiminase; Rheumatoid arthritis
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