Interleukin-17 Cytokines and Receptors: Potential Amplifiers of Tendon Inflammation

Abstract

Interleukin (IL)-17A, a pro-inflammatory cytokine that is linked to the pathology of several inflammatory diseases, has been shown to be upregulated in early human tendinopathy and to mediate inflammatory and tissue remodelling events. However, it remains unclear which cells in tendons can respond to IL-17A, and how IL-17A, and its family members IL-17F and IL-17AF, can affect intracellular signalling activation and mRNA expression in healthy and diseased tendon-derived fibroblasts. Using well-phenotyped human tendon samples, we show that IL-17A and its receptors IL-17RA and IL-17RC are present in healthy hamstring, and tendinopathic and torn supraspinatus tendon tissue. Next, we investigated the effects of IL-17A, IL-17F, or IL-17AF on cultured patient-derived healthy and diseased tendon-derived fibroblasts. In these experiments, IL-17A treatment significantly upregulated IL6, MMP3, and PDPN mRNA expression in diseased tendon-derived fibroblasts. IL-17AF treatment induced moderate increases in these target genes, while little change was observed with IL-17F. These trends were reflected in the activation of intracellular signalling proteins p38 and NF-κB p65, which were significantly increased by IL-17A, modestly increased by IL-17AF, and not increased by IL-17F. In combination with TNF-α, all three IL-17 cytokines induced IL6 and MMP3 mRNA expression to similar levels. Therefore, this study confirms that healthy and diseased tendon-derived fibroblasts are responsive to IL-17 cytokines and that IL-17A induces the most profound intracellular signalling activation and mRNA expression of inflammatory genes, followed by IL-17AF, and finally IL-17F. The ability of IL-17 cytokines to induce a direct response and activate diverse pro-inflammatory signalling pathways through synergy with other inflammatory mediators suggests a role for IL-17 family members as amplifiers of tendon inflammation and as potential therapeutic targets in tendinopathy.

Effectiveness of Lateral Elbow Tendinopathy Treatment Depends on the Content of Biologically Active Compounds in Autologous Platelet-Rich Plasma

“…IL-17 has been shown to mediate the inflammatory response by stimulating the production of pro-inflammatory cytokines and tissue remodeling in human tenocytes. It is proposed as a potential therapeutic target in tendinopathy [42,43]. In our study, we found a negative correlation between IL-17A in the PRP and a functional improvement examined with the PRTEE questionnaire.…”

Interleukin-17 Family Cytokines in Metabolic Disorders and Cancer

“…IL-17A is known to induce the expression of several proinflammatory cytokines. A canonical IL-17 target is IL-6, whose production is augmented when IL-17A acts synergistically with TNFα, which also leads to the production of IL-1β and IL-8 [ 81 , 94 , 95 , 96 , 97 , 98 ]. Additionally, IL-17A acts synergistically with IFNγ to increase the production of IL-8 and monocyte chemoattractant protein-1 (MCP-1) [ 96 , 97 ].…”

“…In addition, IL-17A induces the production of antimicrobial peptides (AMPs), such as β-defensin, and acute phase proteins, such as lipocalin [ 81 , 94 ]. Moreover, tissue remodeling matrix metalloproteinases (MMPs), which can lead to extracellular matrix destruction and tissue damage, are often induced by IL-17A signaling, notably including MMP1, MMP2, MMP3, MMP9, and MMP13 [ 98 , 100 , 104 , 105 , 106 , 107 ]. On the other hand, IL-17A downregulates tissue inhibitors of metalloproteinases (TIMP)1 and TIMP2 [ 106 ].…”

“…IL-17F, although less potently than IL-17A, also induces CCL2, CCL7, TSLP, and MMP13 [ 108 ]. MMP1, MMP3, and MCP1 production also results from stimulation with IL-17F [ 98 , 113 ]. Additionally, when combined with TNFα, IL-17F upregulates the expression of G-CSF, IL-6, and MMP3 [ 4 , 18 , 98 , 108 , 114 ].…”

“…MMP1, MMP3, and MCP1 production also results from stimulation with IL-17F [ 98 , 113 ]. Additionally, when combined with TNFα, IL-17F upregulates the expression of G-CSF, IL-6, and MMP3 [ 4 , 18 , 98 , 108 , 114 ]. IL-17F together with IL-22 also results in the production of mhBD2, as well as other antimicrobial peptides [ 108 , 115 ].…”