New research in Annals of the Rheumatic Diseases has revealed that IL-1β and TNF suppress the expression of histone deacetylase 5 (HDAC5) in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA), an effect that leads to an increase in the production of inflammatory mediators by FLS.

Credit: NPG

Kris Reedquist and colleagues measured gene expression levels in synovial tissues from patients with RA and found that expression of class I histone deacetylase HDAC was associated with expression of inflammatory mediators such as TNF (R = 0.651, P = 0.003) and matrix metalloproteinase-1 (R = 0.502, P = 0.029). By contrast, class IIa HDAC5 was inversely correlated with parameters of disease activity such as erythrocyte sedimentation rate (R = −0.557, P = 0.013), serum levels of C-reactive protein (R = −0.664, P = 0.007) and 28-joint disease activity score (R = −0.567, P = 0.011). Stimulation of FLS with TNF and IL-1β resulted in downregulation of HDAC5, a process that was sufficient and required for the induction of IFNB, CXCL9, CXCL10 and CXCL11 observed after IL-1β stimulation. Furthermore, the researchers found that downregulation of HDAC5 led to increased accumulation of interferon regulatory factor 1 in the nucleus of FLS—a possible mechanism for the induction of type I interferon genes associated with HDAC5 downregulation.

According to Chiara Angiolilli, a co-author of the study, the results “provide strong evidence that HDAC5 can act as a negative regulator of the inflammatory program in FLS”. Moreover, this finding has implications for how individual HDAC family members are studied. “Different HDAC family members will make distinct contributions to pathology in chronic inflammatory diseases such as RA,” explains Reedquist. Further research is needed to define functions for each HDAC family member, potentially adding to our understanding of the pathophysiology of RA and other rheumatic disorders.