IL-1β Enhances Wnt Signal by Inhibiting DKK1

Abstract

Aberrant endochondral bone formation in the physis is a unique bone lesion in neonatal-onset multisystem inflammatory disease (NOMID), also called chronic infantile neurologic cutaneous articular (CINCA), the most severe of the cryopyrin-associated periodic syndrome (CAPS) diseases, which are interleukin-1β (IL-1β)-related monogenic autoinflammatory diseases. The wingless (Wnt) pathway plays an important role in osteoblast differentiation. In this study, we explored the potential role of IL-1β on the expression of WNT genes and the Wnt antagonist Dickkopf-1 (DKK1). The expression of WNT and DKK1 in fibroblast-like synoviocytes (FLS), which are articular resident cells, was quantified by quantitative PCR and enzyme-linked immunosorbent assay. Additionally, we used T cell factor (TCF) reporter assays to evaluate the activity of the canonical Wnt signal pathway in the presence or absence of the supernatant of cultured FLS treated with or without IL-1β and IL-6. Anti-DKK1 antibodies were used to neutralize DKK1. The expression of both canonical and non-canonical WNT genes as well as DKK1 was observed in FLS. The supernatant of cultured FLS suppressed the luciferase activity of the TCF reporter, and this effect was reduced by its pre-treatment with an anti-DKK1 antibody. Both IL-1β and IL-6 significantly reduced DKK1 production. Furthermore, the supernatant of FLS cultured with IL-1β or IL-6 showed a reduced inhibitory effect on Wnt signaling, compared with the supernatant of untreated FLS. These data suggest that IL-1β, like IL-6, dampens DKK1 production, and thereby promotes Wnt signal activation. Therefore, increased levels of IL-1β may contribute to the dysregulation of endochondral ossification in NOMID/CINCA.

The Influence of Pro-Inflammatory Factors on Sclerostin and Dickkopf-1 Production in Human Dental Pulp Cells Under Hypoxic Conditions

“…shows downregulation of SOST and DKK-1. This is in line with another publication in fibroblast-like synoviocytes (Yoshida et al, 2018). Thus, pro-inflammatory molecules might have potential to enhance as well as to downregulate Sost and Dkk-1, depending on the cell type.…”

“…Based on the current knowledge, Sost is also considered an interesting target for therapy in endodontics. Dkk-1 is a contributor to dentin formation and mineralization (Han et al, 2011), it might play a role in root resorption (Zhu et al, 2013) and it is possibly connected to the inflammatory response and bone resorption in periapical lesions (Zhang et al, 2014). Hence, also Dkk-1 could be of interest as target in regenerative endodontic approaches.…”

Differential Effector Response of Amnion‐ and Adipose‐Derived Mesenchymal Stem Cells to Inflammation; Implications for Intradiscal Therapy

“…The difference could be explained in part by the short‐term cytokine data which not only demonstrated elevated levels of IL‐1β produced by AD‐MSC cultures but also higher concentrations of PGE 2 . IL‐1β promotes canonical wnt signaling which is a central intracellular signaling pathway involved in osteogenesis . Moreover, PGE 2 has been shown to be a key cytokine necessary for promoting bone healing and regeneration .…”

“…IL-1β promotes canonical wnt signaling which is a central intracellular signaling pathway involved in osteogenesis. 38 Moreover, PGE 2 has been shown to be a key cytokine necessary for promoting bone healing and regeneration. 39,40 However, to further confirm this hypothesis cytokine analysis on the inflammatory differentiation media at early and late time-points are warranted and intracellular signaling pathway inhibition experiments should be performed.…”

Cancer-associated fibroblasts promote cell proliferation and invasion via paracrine Wnt/IL1β signaling pathway in human bladder cancer

“…Several studies have reported that is a positive regulator of Wnt signaling pathway [11][12][13]. We then hypothesized that CAF-derived may exert its function through regulating Wnt signaling pathway in bladder cancer.…”