Tumor necrosis factor–interleukin‐17 interplay induces S100A8, interleukin‐1β, and matrix metalloproteinases, and drives irreversible cartilage destruction in murine arthritis: Rationale for combination treatment during arthritis

Abstract

Objective. To examine whether synovial interleukin-17 (IL-17) expression promotes tumor necrosis factor (TNF)-induced joint pathologic processes in vivo, and to analyze the surplus ameliorative value of neutralizing IL-17 in addition to TNF during collageninduced arthritis (CIA).Methods. Adenoviral vectors were used to induce overexpression of IL-17 and/or TNF in murine knee joints. In addition, mice with CIA were treated, at different stages of arthritis, with soluble IL-17 receptor (sIL-17R), TNF binding protein (TNFBP), or the combination.Results. Overexpression of IL-17 and TNF resulted in joint inflammation and bone erosion in murine knees. Interestingly, IL-17 strikingly enhanced both the joint-inflammatory and joint-destructive capacity of TNF. Further analysis revealed a strongly enhanced up-regulation of S100A8, IL-1␤, and matrix metalloproteinase (MMP) messenger RNA, only when both TNF and IL-17 were present. Moreover, the increase in irreversible cartilage destruction was not merely the result of enhanced inflammation, but also was associated with a direct synergistic effect of these cytokines in the joint. S100A9 deficiency in mice protected against IL-17/TNF-induced expression of cartilage NITEGE neoepitopes. During established arthritis, the combination of sIL-17R and TNFBP was more effective than the anticytokine treatments alone, and significantly inhibited further joint inflammation and cartilage destruction.Conclusion. Local synovial IL-17 expression enhances the role of TNF in joint destruction. Synergy between TNF and IL-17 in vivo results in striking exaggeration of cartilage erosion, in parallel with a synergistic up-regulation of S100A8, IL-1␤, and erosive MMPs. Moreover, neutralizing IL-17 in addition to TNF further improves protection against joint damage and is still effective during late-stage CIA. Therefore, compared with anti-TNF alone, combination blocking of TNF and IL-17 may have additional therapeutic value for the treatment of destructive arthritis.Rheumatoid arthritis (RA) is a chronic disorder with unknown etiology. It is characterized by autoimmunity, infiltration of joint synovium by activated inflammatory cells, synovial hyperplasia, and progressive destruction of cartilage and bone. In the last decade, Supported by grants from the Dutch Arthritis Association (NR 00-1-302) and from the Stichting De Drie Lichten,

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

“…Remarkably, when both IFNAR1 and TNFR1 signaling are impaired, each marker follows one of the single KO phenotypes, except for S100a8, which is less induced in DKO mice compared with the single KO mice, indicating that its induction is dependent on both pathways. However, TNF and IL-17 have been reported to induce S100a8 synergistically (49,50). Because IL-17F is reduced in both TNFR1 KO and IFNAR1 KO mice, this raises the question whether the reduced IL-17F levels affect the expression of S100a8 in DKO mice as well.…”

IL-23R rs11209026 polymorphism modulates IL-17A expression in patients with rheumatoid arthritis

“…20,21 The reason why IL-17A is only present in a subgroup of patients remains unclear. However, RA is a heterogeneous disease and the presence of IL-17A clearly defines a specific subgroup of patients who appear to have more aggressive disease, with evidence that the presence of IL-17 results in more joint erosion 22 and may predict vascular function in RA. 20 As such, we undertook our analysis in the subgroup of patients with detectable levels of IL-17A.…”

Interleukin-17 augments tumor necrosis factor α-mediated increase of hypoxia-inducible factor-1α and inhibits vasodilator-stimulated phosphoprotein expression to reduce the adhesion of breast cancer cells

“…A previous study has established that the combination of IL-17 and TNF-α induces the activation of certain genes, including HIF-1α (13), neutrophil gelatinase-associated lipocalin (14), whereas IL-17 or TNF-α alone did not produce a significant effect. Other previous studies (15,16,18) have also demonstrated that IL-17 augments TNF-α-induced gene expression, including G-CSF, GM-CSF, KC, MIP-2, PGE2 and VEGF. A potential underlying mechanism that has been hypothesized is that IL-17 may promote the stability of TNF-α-induced mRNA (7).…”

“…A previous study has suggested the potential hypothesis that IL-17 may promote the stability of TNF-α-induced mRNA (17). However, previous studies investigating the combination of IL-17 and TNF-α have focused on inflammatory angiogenesis (16), investigating the role of these cytokines in inflammation (14,15) and autoimmune diseases, including rheumatoid arthritis (13,18) and psoriasis (19). Therefore, the current study focused on the combination of IL-17 and TNF-α and its effect on tumor cells.…”