Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo

Abstract

Posttranscriptional regulation of IL-6 has been largely uncharacterized, with the exception of the ribonuclease Regnase-1, which prevents autoimmunity by destabilizing IL-6 mRNA. Here, we identified AT-rich interactive domain-containing protein 5A (Arid5a) as a unique RNA binding protein, which stabilizes IL-6 but not TNF-α mRNA through binding to the 3′ untranslated region of IL-6 mRNA. Arid5a was enhanced in macrophages in response to LPS, IL-1β, and IL-6. Arid5a deficiency inhibited elevation of IL-6 serum level in LPStreated mice and suppressed IL-6 levels and the development of T H 17 cells in experimental autoimmune encephalomyelitis. Importantly, Arid5a inhibited the destabilizing effect of Regnase-1 on IL-6 mRNA. These results indicate that Arid5a plays an important role in promotion of inflammatory processes and autoimmune diseases.immune regulation | RNA-protein complex

IL-6 in Inflammation, Immunity, and Disease

“…We have recently identified a novel RNAbinding protein, AT-rich interactive domaincontaining protein 5a (Arid5a), which binds to the 3 0 UTR of IL-6 mRNA, resulting in the selective stabilization of IL-6 but not of TNF-a or IL-12 mRNA (Masuda et al 2013). Arid5a expression was found to be enhanced in macrophages in response to LPS, IL-1b, and IL-6, and also to be induced under Th17-polarizing conditions in T cells.…”

The Biology and Medical Implications of Interleukin-6

“…Recently, we have identified a novel RNA-binding protein termed AT-rich interactive domain-containing protein 5a (Arid5a), which binds to the 3 0 -UTR of the IL-6 mRNA, resulting in the selective stabilization of IL-6, but not of TNF-a or IL-12 mRNA (19). The expression of Arid5a is increased in macrophages in response to lipopolysaccharide (LPS), IL-1b, or IL-6, and it is also induced under Th17-polarizing conditions in T cells.…”

Programmed cell senescence: role of IL-6 in the pituitary

“…The IL-6 promoter contains motifs for the binding of AP-1, cyclic AMP, C/EBPβ, Sp1, CREB, STAT3 and NF-κB (Lee et al 1987, Matsusaka et al 1993, Kishimoto 2005, Gerlo et al 2008, Spooren et al 2010). IL-6 transcript is positively regulated by Arid 5a (Masuda et al 2013), TNFα and IL-1β (Gruys et al 2005), and negatively regulated by regnase-I (Iwasaki et al 2011), bromodomain-containing protein 4 (BRD4) (Barrett et al 2014), and microRNAs (miRs) e.g. miR-26a (Yang et al 2013), miR-142 (Sun et al 2013), miR-146a (He et al 2014), miR-146b (Xiang et al 2014), miR-187 (Rossato et al 2012), miR-200s (Dou et al 2013) and miR-329 (Garg et al 2013) (Fig.…”