Background/Purpose: IL-33 is a new member of the IL-1 cytokine family. Recent studies in an animal model of murine collagen-induced arthritis and human rheumatoid arthritis (RA) have suggested that IL-33 may be important as an endogenous danger signal (alarmin) in the pathogenesis of RA. IL-33 mRNA and protein expression are induced in RA fibroblast-like synoviocytes (FLS) following TNF-α/IL-1β stimulation, and IL-33 protein is mainly detected in the nucleus of these cells. The nuclear localization of IL-33 in IL-1β/TNF-α stimulated cells suggests that it may have a regulatory function inside the cell, as has been shown previously for IL-1α and IL-1F7b. The purpose of our study was to analyze the role of extracellular and intracellular IL-33 as an alarmin or regulator of nuclear transcription in RA FLS.

Methods: Synovial tissues from RA patients fulfilling the ACR criteria were obtained during open joint replacement. RA synovial samples were digested, subsequently cultured for 7 days and 3-passaged cells were used for all experiments. For analysis, quantitative RT-PCR, confocal analysis, western blot analysis, and ELISA were performed.

Results: IL-33 and ST2 (receptor of IL-33) mRNA expression increased in RA FLS stimulated with poly I:C (10 ug/ml) as a TLR3 ligand, IL-1β (10 ng/ml), and TNF-α (10 ng/ml). However, IL-33 release was not detected in the culture supernatant. Similar to previous observations, IL-33 was released from damaged FLS. After identification of the ST2 on FLS by confocal analysis, FLS was stimulated with IL-33. Exogenous IL-33 stimulation (10 – 100 ng/ml) of RA FLS increased IP-10 and RANKL mRNA expression and treatment with anti-ST2 blocked this expression. The role of intracellular IL-33 as a nuclear protein was evaluated using IL-33 siRNA. Silencing of IL-33 increased MMP-1, 3, 13, IL-6, 8, and MCP-1 mRNA expression compared to the scrambled control in RA FLS stimulated with poly I:C, IL-1β, and TNF-α. In addition, we observed that the silencing of IL-33 induced significant degradation of IκBα and increased of NF-κB activity. These findings reveal a novel role for IL-33 as a negative modulator of NF-κB activity.

Conclusion: IL-33 has dual, opposing functions. As a pro-inflammatory cytokine, IL-33 induced the expression of IP-10 and RANKL mRNA. These effects may induce bone erosion by enhancing osteoclastogenesis in RA. In contrast to extracellular IL-33, intracellular IL-33 acted as negative modulator of NF-κB activity and suppressed the expression of many pro-inflammatory cytokines and pro-destructive molecules in RA FLS.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dual-function-of-interleukin-33-in-fibroblast-like-synoviocytes-in-patients-with-rheumatoid-arthritis/