miR-708 Negatively Regulates TNF α/IL-1 β Signaling by Suppressing NF- κ B and Arachidonic Acid Pathways

Abstract

Two pathways commonly dysregulated in autoimmune diseases and cancer are tumor necrosis factor alpha (TNFα) and interleukin 1 beta (IL-1β) signaling. Researchers have also shown that both signaling cascades positively regulate arachidonic acid (AA) signaling. More specifically, TNFα/IL-1β promotes expression of the prostaglandin E2- (PGE₂-) producing enzymes, cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1). Exacerbated TNFα, IL-1β, and AA signaling have been associated with many diseases. While some TNFα therapies have significantly improved patients' lives, there is still an urgent need to develop novel therapeutics that more comprehensively treat inflammatory-related diseases. Recently, researchers have begun to use RNA interference (RNAi) to treat various diseases in the clinic. One type of RNAi is microRNA (miRNA), a class of small noncoding RNA found within cells. One miRNA in particular, miR-708, has been shown to target COX-2 and mPGES-1. Previous studies have also suggested that miR-708 may be a negative regulator of TNFα/IL-1β signaling. Therefore, we studied the relationship between miR-708, TNFα/IL-1β, and AA signaling in diseased lung cells. We found that miR-708 negatively regulates TNFα/IL-1β signaling in nondiseased lung cells, which is lost in diseased lung cells. Transient transfection of miR-708 suppressed TNFα/IL-1β-induced changes in COX-2, mPGES-1, and PGE₂ levels. Moreover, miR-708 also suppressed TNFα/IL-1β-induced IL-6 independent of AA signaling. Mechanistically, we determined that miR-708 suppressed IL-6 signaling by reducing expression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activator inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ). Collectively, our data suggest miR-708 regulates TNFα/IL-1β signaling by inhibiting multiple points of the signaling cascade.