Alogliptin inhibits IL-1β-induced inflammatory response in fibroblast-like synoviocytes

Highlights

• Alogliptin reduced IL-1β- induced increase of ROS and decrease of GSH in FLSs.

• Alogliptin reduced IL-1β- induced MMP-3, MMP-13, NF-κα, IL-6, and IL-8 in FLSs.

• Alogliptin suppressed IL-1β- induced the activation of JNK/AP-1 in FLSs.

• Alogliptin inhibited IL-1β- induced the activation of IKK/IκBα/NF-κB in FLSs.

Abstract

Excessive production of pro-inflammatory cytokines such as interleukin (IL)-1β plays an important role in the chronic inflammation in fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). Alogliptin, an important selective dipeptidyl peptidase-4 (DPP-4) inhibitor licensed for the treatment of type 2 diabetes, has displayed a wide range of pharmacological capacities. In the present study, we aimed to investigate whether alogliptin possessed a protective effect against IL-1β-induced insult in FLS. Our results indicate that alogliptin treatment ameliorated IL-1β-induced production of reactive oxygen species, the expression of matrix metalloproteinase-3 (MMP-3) and MMP-13, secretions of tumor necrosis factor-α (TNF-α), IL-6, and IL-8. Additionally, we found that alogliptin inhibited c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) signaling by reducing IL-1β-induced phosphorylation of JNK, the expression of c-Jun and c-Fos, and the luciferase activity of AP-1. Importantly, alogliptin suppressed IL-1β-induced activation of IκBα/NF-κB signaling by preventing the phosphorylation and degradation of IκBα, nuclear translocation of NF-κB p65, as well as the luciferase activity of AP-1. These findings suggest that alogliptin might have therapeutic potential for the treatment of chronic inflammation in RA.

Introduction

Rheumatoid arthritis (RA) is one of the most common autoimmune and chronic inflammatory diseases worldwide. It is pathologically characterized by increased synovial inflammation and the destruction of bone and joint tissues [20], [8]. Several risk factors have been associated with the progression and development of RA, including genetics, environmental factors, and inflammatory conditions [9]. A diversity of cytokines has been associated with the pathological development of RA including IL-1β, TNFα, IL-6, IL-15, IL-17, and IL-18 [42]. Among them, IL-1β and TNF act as key mediators in the pathogenesis of RA. IL-1β is abundantly expressed in the synovial membrane, where it directly activates FLS and contributes joint destruction and bone resorption [10]. Plasma and synovial fluid concentrations of IL-1β in RA patients are elevated [17].

Dysregulation of fibroblast-like synoviocytes (FLS) plays a causal role in the occurrence and pathogenesis of RA [4]. FLS have been reported to participate in the initiation of RA through producing pro-inflammatory cytokines and chemokines, including interleukin (IL)-1β [14]. Long-term exposure to inflammatory factors results in a phenotypic conversion of normal FLS to RA-FLS. RA-FLS represent a pathological phenotype that can perpetuate joint disorders through various mechanisms [20]. Exacerbation of oxidative stress with increased production of reactive oxygen species has been found in RA-FLS. Importantly, RA-FLS also produce excessive matrix metalloproteinases (MMPs), including MMP-3 and MMP-13, which can induce the degradation of extracellular matrix (ECM) [19]. Multiple signaling pathways have been shown to be involved in the inflammatory response progression of synovitis, including the mitogen-activated protein kinase (MAPK) p38 and the nuclear factor-κB (NF-κB) pathways, which have become therapeutic targets for the treatment of RA [27].

IL-1β is an important cytokine involved in the pathogenesis of RA. IL-1β has been reported to be increased in the synovium and synovial fluid of patients with RA. IL-1β contributes to the development of RA by causing oxidative stress, production of proinflammatory cytokines and chemokines, and expression of degradative enzymes by FLS, thereby promoting pannus invasion and sustained inflammation [11], [46]. Importantly, IL-1β has been linked with the pathogenic interplay between inflammation and metabolic disorders, as it has been implicated in the pathogenic mechanisms of both RA and type 2 diabetes mellitus (T2DM). Intriguingly, the potential role of anti-IL-1β drugs has been proposed in RA patients affected by T2DM [34]. However, the results of a recent random trial indicate that anti-IL-1β drugs appear to be effective only in patients with both RA and T2DM, suggesting that the IL-1β pathway could play a more important role in patients with RA and T2DM than for those with RA alone [35].

Alogliptin, an important member of the selective dipeptidyl peptidase-4 (DPP-4) inhibitor family, has been licensed for the treatment of T2DM [7]. Alogliptin is able to improve glycemic control by increasing the secretion of glucagon-likepeptide1 (GLP-1). In addition to lowering glucose levels in T2DM patients, alogliptin has displayed a wide range of pharmacological capacities in various diseases, such as atherosclerosis and vascular inflammation [5]. A recent study reported that treatment with alogliptin can improve longevity and health in rodents fed a high-fat diet by decreasing organ pathology, preserving mitochondrial function, and suppressing oxidative stress [52]. Another study demonstrated that alogliptin can alleviate liver fibrosis via regulation of hepatic stellate cell (HSC) activation [47], [51]. Interestingly, administration of DPP-4 inhibitors alleviates lipopolysaccharide (LPS)-induced bone resorption by reducing osteoclast formation [15]. Treatment with alogliptin was recently reported to ameliorate TNF-α-induced degradation of extracellular matrix by suppressing MMP-1, −3, and −13, ADAMTS-4 and −5, and NF-κB signaling in human primary chondrocytes, suggesting that alogliptin may be used as an effective preventative therapy against continued destruction of the articular ECM in osteoarthritis (OA) [47], [51]. However, as far as the authors know, the possible effects of alogliptin in RA and FLS dysfunction have not yet been reported. Due to the important role of IL-1β in the pathogenic interplay between RA and T2DM, in the current study, we aimed to investigate whether alogliptin exerts a protective effect against IL-1β-induced insults in FLS.