The Mechanisms and Significances of Synergistic Effects of Mycophenolic Acid and LPS on IL-1β Secretion by Mononuclear

Lupus Nephritis

To determine the mechanisms and significances of synergistic effects of mycophenolic acid and LPS on IL-1β secretion by mononuclear

Mycophenolate mofetil (MMF), which inhibits T and B lymphocyte proliferation, is widely used to treat a variety of autoimmune diseases, such as systemic lupus erythematosus (SLE) and lupus nephritis (LN). We are the first to show that mycophenolic acid (MPA), the active metabolite of MMF, in association with lipopolysaccharide (LPS), is able to promote the secretion of interleukin (IL)-1β, which contradicts the traditional conception that immunosuppressants inhibit the secretion of inflammatory factors. In this study, we first determined the effects of MPA in association with LPS on IL-1β production. Then, we explored whether the synergized effect on IL-1β production was mediated through the nuclear factor （NF）-κB pathway that produces more pro-IL-1β, or through the triggering of NLRP3 inflammasome that leads to enhanced activation of caspase-1 and accelerated degradation of pro-IL-1β into mature IL-1β. This study is not only conducive to clarify the mechanisms, signal transduction pathways and potential clinical significances of IL-1β production in LPS and MPA combined treatment, but also to provide experimental data as well as theoretical rationales for more effective and more logical immunosuppressive protocols.

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