Interleukin (IL)-17A, F and AF in inflammation: a study in collagen-induced arthritis and rheumatoid arthritis

Abstract

Interleukin (IL)-17 plays a critical role in inflammation. Most studies to date have elucidated the inflammatory role of IL-17A, often referred to as IL-17. IL-17F is a member of the IL-17 family bearing 50% homology to IL-17A and can also be present as heterodimer IL-17AF. This study elucidates the distribution and contribution of IL-17A, F and AF in inflammatory arthritis. Neutralizing antibody to IL-17A alone or IL-17F alone or in combination was utilized in the mouse collagen-induced arthritis (CIA) model to elucidate the contribution of each subtype in mediating inflammation. IL-17A, F and AF were all increased during inflammatory arthritis. Neutralization of IL-17A reduced the severity of arthritis, neutralization of IL-17A+IL-17F had the same effect as neutralizing IL-17A, while neutralization of IL-17F had no effect. Moreover, significantly higher levels of IL-17A and IL-17F were detected in peripheral blood mononuclear cells (PBMC) from patients with rheumatoid arthritis (RA) in comparison to patients with osteoarthritis (OA). IL-17A and AF were detected in synovial fluid mononuclear cells (SFMC) in RA and OA, with IL-17A being significantly higher in RA patients. Enriched CD3+ T cells from RA PBMCs produced singnificantly high levels of IL-17A and IL-17AF in comparison to OA peripheral blood CD3+ T cells. IL-17A, F and AF were undetectable in T cells from SFMCs from RA and OA. While IL-17A, F, and AF were all induced during CIA, IL-17A played a dominant role. Furthermore, production of IL-17A, and not IL-17F or IL-17AF, was elevated in PBMCs, SFMCs and enriched peripheral blood CD3+ T in RA.

T Cells in Osteoarthritis: Alterations and Beyond

“…Nevertheless, it is widely accepted that Th17 cells are present in the synovial fluid and synovial membranes of OA patients. For example, in addition to the strong expression of IL-17 mRNA in the synovial membranes of OA patients (69), a high level of IL-17 has been measured in the synovial fluid of OA patients, whereas both are below the limit of detection in healthy subjects (31, 70). In addition, Th17 cells have been detected in the joints of OA patients, albeit in smaller numbers than in RA joints (40).…”

A Heterodimeric Cytokine, Consisting of IL-17A and IL-17F, Promotes Migration and Capillary-Like Tube Formation of Human Vascular Endothelial Cells

“…IL-17A has been demonstrated to participate in the pathological angiogenesis in rheumatoid arthritis, psoriasis and tumors (Numasaki et al 2005;Kim et al 2013;Varricchi et al 2015). In addition, IL-17A/F is expressed at the lesion of psoriasis, chronic obstructive pulmonary disease and rheumatoid arthritis (Chang et al 2014;Kakeda et al 2014;Sarkar et al 2014). Although the biological activities of IL-17A/F to promote angiogenesis-related endothelial cell functions seem to be slightly lower than those of IL-17A, IL-17A/F may also contribute to the pathological angiogenesis characterized in rheumatoid arthritis and psoriasis.…”

Presence, function, and regulation of IL‐17F‐expressing human CD4+ T cells

“…Both IL-17A [14][15][16][17] and IL-17F [14,16,17] can amplify their inflammatory potential by synergizing with other cytokines including TNF-α. In both the mouse collagen-induced arthritis (CIA) and EAE model, blockade of IL-17F did not exhibit an effect, whereas blockade of IL-17A reduced inflammation and disease severity [12,18]. Dual IL-17A and IL-17F blockade in CIA had little additional effect compared to blockade of IL-17A alone [18].…”