TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a

Abstract

The AT-rich interactive domain-containing protein 5a (Arid5a) plays a critical role in autoimmunity by regulating the half-life of Interleukin-6 (IL-6) mRNA. However, the signaling pathways underlying Arid5a-mediated regulation of IL-6 mRNA stability are largely uncharacterized. Here, we found that during the early phase of lipopolysaccharide (LPS) stimulation, NF-κB and an NF-κB-triggered IL-6-positive feedback loop activate Arid5a gene expression, increasing IL-6 expression via stabilization of the IL-6 mRNA. Subsequently, mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) promotes translocation of AU-rich element RNA-binding protein 1 (AUF-1) from the nucleus to the cytoplasm, where it destabilizes Arid5a mRNA by binding to AU-rich elements in the 3΄ UTR. This results in downregulation of IL-6 mRNA expression. During the late phase of LPS stimulation, p38 MAPK phosphorylates Arid5a and recruits the WW domain containing E3 ubiquitin protein ligase 1 (WWP1) to its complex, which in turn ubiquitinates Arid5a in a K48-linked manner, leading to its degradation. Inhibition of Arid5a phosphorylation and degradation increases production of IL-6 mRNA. Thus, our data demonstrate that LPS-induced NF-κB and MAPK signaling are required to control the regulation of the IL-6 mRNA stabilizing molecule Arid5a. This study therefore substantially increases our understanding of the mechanisms by which IL-6 is regulated.

Knockdown XIST alleviates LPS‐induced WI‐38 cell apoptosis and inflammation injury via targeting miR‐370‐3p/TLR4 in acute pneumonia

“…Notably, previous studies have suggested that TLR4 signalling can promote injury, inflammation, and pulmonary fibrosis in acute or chronic lung injury mice model . TLR4 recruits signal transducers and initiates signal cascades through ligand binding, which can active NF‐κB pathway and promote the production of inflammatory factors, such as IL‐6 and TNF‐α . Meanwhile, the JAK/STAT signalling pathway has been involved in pathological inflammatory response .…”

Toll‐like receptor 4 regulates spontaneous intestinal tumorigenesis by up‐regulating IL‐6 and GM‐CSF

“…These data suggest that TLR4 was the upstream molecule of IL6 that promoted tumour development, and it has been reported that TLR4 and NF-κB signalling are required to control the regulation of the IL-6 mRNA stabilizing molecule Arid5a. 34 GM-CSF was initially classified as a haematopoietic growth factor. In the inflammatory process, GM-CSF serves as a communication conduit between tissue-invading lymphocytes and myeloid cells, and GM-CSF-activated phagocytes are well equipped to cause tissue damage.…”

Melatonin promotes neuroblastoma cell differentiation by activating hyaluronan synthase 3‐induced mitophagy

“…A previous study demonstrated that berberine, a plant alkaloid, induces neuronal differentiation accompanied by increases in differentiation markers such as MAP2, TUBB3 and NCAM in N2a cells . Additionally, TLR4 plays a key role in activating NF‐ κ B‐mediated effects to trigger the differentiation of glioblastoma stem‐like cells . HA (100 μg/mL) synthesized by HAS3 is a main component of the brain extracellular matrix, and effectively triggers the TLR4‐NF‐κB pathway in differentiating glioblastoma stem‐like cells .…”