IL-1β Enhances Wnt Signal by Inhibiting DKK1

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.