Aberrant Low Expression of A20 in Tumor Necrosis Factor-α-stimulated SLE Monocytes Mediates Sustained NF-κB Inflammatory Response

The aberrantly activated monocytes and nuclear factor-kappaB (NF-kappa B) pathway contribute to the pathogenesis of systemic lupus erythematosus (SLE), and the aberrantly activated NF-kappa B is associated with defects in the anti-inflammatory A20 in SLE. However, whether SLE monocytes express A20 and whether the A20 expression under sustained proinflammatory stimulation is altered to contribute to the uncontrolled NF-kappa B inflammatory response are unclear. In this study, we found that the freshly isolated monocytes from SLE patients and healthy controls did not differ in expression levels of IL-1 beta, I kappa B alpha and A20. After TNF-alpha stimulation for 48 h, the monocytes from both groups expressed higher levels of IL-1 beta and I kappa B alpha than the monocytes without TNF-alpha treatment. Although the increased levels of NF-kappa B were observed in the nucleus of both the SLE and control monocytes after 24 h of TNF-alpha stimulation, the enhancement in SLE monocytes was significantly more robust than in the control monocytes. In addition, while the p-I kappa B alpha level in healthy monocytes was increased, the p-I kappa B alpha level in SLE monocytes was slightly decreased after TNF-alpha stimulation. Interestingly, after TNF-alpha treatment, the A20 expression in SLE monocytes was not markedly altered compared with the untreated SLE monocytes; moreover, the SLE monocytes expressed significantly lower A20 than healthy monocytes with TNF-alpha treatment at each time point. Results in this study demonstrate that TNF-alpha activates a significant NF-kappa B inflammatory response in SLE monocytes, which is at least partially mediated by the aberrantly low expression of A20 upon TNF-alpha stimulation, contributing to the prolonged inflammatory response in SLE.