Cleophas M.T.J.1,2, Crişan T.O.1,2, Dinarello C.A.1,5, Hoogerbrugge N.3, Netea-Maier R.T. 4, Netea M.G.1,2, Joosten L.A.B.1,2
1Department of Internal Medicine, 2Radboud Institute for Molecular Life Sciences, 3Department of Human Genetics, and 4Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands 5Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Acute gout is a highly common and painful form of inflammatory arthritis, occurring mainly in men above the age of 50. The recurring flares of arthritis are elicited by monosodium urate (MSU) crystal deposits in the joints that, in the presence of a secondary stimulus, can induce synergistic cytokine production. Sodium butyrate can inhibit MSU-induced cytokine production via broad inhibition of class I histone deacetylases (HDACs), which includes HDAC1, -2, -3, and -8. HDACs could therefore be an important target for new therapies against gout. Our aim is to further pinpoint the HDAC(s) involved in MSU-induced cytokine production. Primary peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors and Cowden syndrome patients. The cells were pre-incubated with a highly specific HDAC1/2 inhibitor, Romidepsin, or other metabolic inhibitors and stimulated with a combination of palmitic acid (C16.0) and MSU crystals. Cytokine levels were measured by ELISA, transcription was measured with qPCR. Romidepsin potently inhibited C16.0+MSU-induced inflammatory cytokines in healthy volunteers. It furthermore induced transcription of PTEN, a negative regulator of PI3K/Akt signaling, and CPT1A, a β-oxidation enzyme that is down-regulated by Akt. However, Romidepsin had a similar cytokine-suppressive effect in PBMCs isolated from Cowden syndrome patients, who have a germline loss-of-function mutation in the PTEN gene. Additionally, inhibiting glycolysis with 2-deoxy-D-glucose decreased C16.0+MSU-induced cytokine production, and inhibition of β-oxidation with etomoxir increased it. These results suggest that Romidepsin inhibits MSU-induced cytokine production by restoring cellular energy homeostasis, possibly by inhibiting Akt signaling. However, PTEN does not play a role in the anti-inflammatory effects of Romidepsin. The up-regulation of PTEN gene transcription in healthy volunteers may well be a secondary response to Romidepsin effects. With these results, we provide a rationale for HDAC1/2 inhibition as a potent anti-inflammatory treatment which may have beneficial effects in acute gout.
References: Cleophas MC, Crisan TO, Lemmers H, et al. Suppression of monosodium urate crystal-induced cytokine production by butyrate is mediated by the inhibition of class I histone deacetylases. Ann Rheum Dis 2015. This research is supported by the Dutch Arthritis Foundation (12-2-303).