Multifaceted role of IL‐21 in rheumatoid arthritis: Current understanding and future perspectives

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disorder designated with hyperplastic synovium, bone destruction and cartilage degradation. Current therapies involve targeting major cytokines and inflammatory mediators involved in RA to alleviate the pain and provide a temporary relief. Interleukin 21 (IL-21), a recently identified cytokine is known to possess a versatile role in modulating the cells of the RA synovium. Over the past decade, the pleiotropic role of IL-21 in RA pathogenesis has been implicated in several aspects. T helper 17 (Th17) and follicular T helper cells (Tfh), being the key immunomodulators of the RA synovium secrete high amounts of IL-21 during disease progression. Several studies have provided experimental evidences elucidating the multifaceted role of IL-21 in RA disease progression. IL-21 has the potential to activate T cells, B cells, monocytes/macrophages and synovial fibroblasts in RA pathogenesis through activation of JAK-STAT, MAPK and PI3K/Akt signaling pathways. Till date, therapies targeting Th17 cells and its inflammatory cytokines have been under investigation and are subjected to various clinical trials. This review showcases the role of IL-21 in RA pathogenesis and recent reports implicating its function in various immune cells, major signaling pathways, and in promoting osteoclastogenesis.

Interleukin‐21 enhances Toll‐like receptor 2/4‐mediated cytokine production via phosphorylation in the STAT3, Akt and p38 MAPK signalling pathways in human monocytic THP‐1 cells

“…IL‐21 plays pivotal roles in modulating the function of various immune cells and is involved in the pathogenesis of many autoimmune diseases, especially RA . IL‐21 regulates the differentiation and proliferation of T and B cells, mediates the proliferation of cytotoxic natural killer (NK) cells, and promotes osteoclastogenesis in RAW264.7 cells .…”

The Janus kinase 1/2 inhibitor baricitinib reduces biomarkers of joint destruction in moderate to severe rheumatoid arthritis

“…Joints exhibit the cartilage loss and bone erosions of the subchondral bone, leading to loss of joint function and disability [1,2]. Disease progression in RA is driven largely by the effects of pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha [2] as well as IL-21 [3], continuously secreted by immune cells in an inflammatory environment. Through activation of their receptors, these cytokines initiate signaling cascades which include the activation of downstream Janus kinase (JAK), spleen tyrosine kinase, and mitogen-activated protein kinase resulting in the increased expression of proteolytic enzymes such as matrix metalloproteinases (MMPs) [4].…”

Adenovirus‑mediated overexpression of interleukin‑21 regulates the development of oral squamous cell carcinoma in vitro

“…ab192623; 1:2,000) were obtained from Abcam. 6 , cells were infected with 1x10 8 µg Ad-null or Ad-IL-21 by polybrene (Sigma) and the control cells were treated with PBS for 24 h at 37˚C. Immunohistochemical (IHC) analysis.…”

“…Cell migration assay. The infected CAL-27 cells were plated into 10 cm dish at a density 5x10 6 and cultured for 24 h. Subsequently, the cells were scraped with a 200-µl pipette tip and washed with PBS three times, prior to being cultured in DMEM without FBS. The images of the scratch wounds were captured at 0 or 24 h using a confocal microscope (magnification, x400).…”

“…Interleukin-21 (IL-21) is a member of the γ chain cytokine family, which is mainly produced by activated CD4 + T cells and natural killer (NK) cells (6). IL-21 can regulate the innate and adaptive immune response, which have been found to serve a diverse range of important roles in inflammation and tumor progression (7).…”