Background/Purpose

Gouty arthritis is triggered by endogenously formed monosodium urate (MSU) crystals. MSU crystals alone are unable to induce cytokine production and therefore a second stimulus is needed to induce the release of active interleukin (IL)-1β, the dominant cytokine in acute gout. Toll-like receptor (TLR) ligands such as LPS or saturated free fatty acids (FFA) can provide such a second signal and stimulate transcription of pro-IL-1β. In contrast to FFA, which can act as second signal for MSU-mediated cytokine production, the short-chain fatty acid butyrate has many anti-inflammatory effects. One of the possible mechanisms involved is inhibition of histone deacetylases (HDACs). Here, we explored the effects of butyrate on MSU/FFA-induced cytokine production and its inhibition of several specific HDACs.

Methods

Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors or gouty arthritis patients and stimulated for 24 hours with MSU and palmitic acid (C16.0) in the presence or absence of butyrate or the synthetic HDAC inhibitors. Cytokine responses were measured with specific ELISAs and quantitative PCR. Effects on HDAC activity were measured with a fluorimetric cellular assay kit.

Results

Butyrate decreased C16.0/MSU-induced production of IL-1b, IL-6, and IL-8, as well as the transcription of IL-1b mRNA. Similar results were obtained when PBMCs isolated from gout patients were exposed to butyrate and C16.0/MSU. Butyrate selectively inhibited class I HDACs, but the strongest inhibition was found for HDAC8. However, the selective HDAC8 inhibitor ITF-A did not decrease ex-vivo C16.0/MSU-induced IL-1b production. The pan HDAC inhibitor Panobinostat and the HDAC inhibitor ITF-B significantly decreased C16.0/MSU-induced IL-1b production. Interestingly, the dose-response curves of butyrate and ITF-B are very different between PBMC’s stimulated with C16.0/MSU or with LPS.

Conclusion

Butyrate and ITF-B have in common that they both inhibit class I HDACs and potently inhibit C16.0/MSU-induced IL-1b production. ITF-B also inhibits HDAC10 and -11, but the effect on C16.0/MSU- and LPS-induced IL-1b production is strikingly similar to that of butyrate. Therefore we conclude that the effect of butyrate on C16.0/MSU-induced cytokine production is mediated through class I HDAC inhibition. In contrast to the high concentrations of butyrate needed for cytokine suppression, synthetic HDAC inhibitors show potent anti-inflammatory effects at low concentrations. These novel HDAC inhibitors could be effective in the treatment of acute gout. Moreover, the use of specific HDAC inhibitors could even improve the efficacy and reduce any potential adverse effects.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/suppressive-effect-of-butyrate-on-monosodium-urate-msu-crystal-induced-il-1beta-production-is-mediated-via-inhibition-of-class-i-histone-deacetylases/