Abstract
The anti-inflammatory cytokine interleukin-10 (IL10) is essential for attenuating inflammatory responses, which includes reducing the expression of pro-inflammatory microRNA-155 (miR155) in lipopolysaccharide (LPS) activated macrophages. miR155 enhances the expression of pro-inflammatory cytokines such as TNFα and suppresses expression of anti-inflammatory molecules such as SHIP1 and SOCS1. We previously found that IL10 interfered with the maturation of pre-miR155 to miR155. To understand the mechanism by which IL10 interferes with pre-miR155 maturation we isolated proteins that associate with pre-miR155 in response to IL10 in macrophages. We identified CELF2, a member of the CUGBP, ELAV-Like Family (CELF) family of RNA binding proteins, as protein whose association with pre-miR155 increased in IL10 treated cells. CRISPR-Cas9 mediated knockdown of CELF2 impaired IL10's ability to inhibit both miR155 expression and TNFα expression.
Highlights
MicroRNAs are small noncoding RNAs originally discovered in Caenorhabditis elegans, involved in the regulation of cell proliferation and differentiation in early embryonic development [1]
Both of these RNA binding proteins were first described as ones which bind to the AU-rich element (ARE) in the 3’-untranslated region in the TNFα mRNA [26, 27] and the TNFα ARE is required for IL10 control of TNFα mRNA expression [9, 28]
CELF2 belongs to the CUG-BP, Elav-like family (CELF) and has been shown to possess numerous RNA regulatory activities such as mRNA binding, RNA editing, translation inhibition and alternative splicing in different tissues such as neurons, heart, muscle and kidney [32,33,34,35,36]
Summary
MicroRNAs (miRNA) are small noncoding RNAs originally discovered in Caenorhabditis elegans, involved in the regulation of cell proliferation and differentiation in early embryonic development [1]. Since hundreds of miRNAs have been identified in the human genome, as they play critical roles in post-transcriptional regulation of gene expression in diverse cell types and affiliated cellular pathways [2]. There is increasing attention to the role of miRNAs, and miR155 in particular, in inflammatory responses induced by pathogenassociated molecular pattern such as the bacteria cell wall component lipopolysaccharide (LPS) [3, 4]. O’Connell et al found that the upregulation of miR155 increased production of the inflammatory cytokine TNFα from LPS stimulated macrophages [3].
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