LIN28B-AS1-IGF2BP1 association is required for LPS-induced NFκB activation and pro-inflammatory responses in human macrophages and monocytes

Insulin-like growth factor 2 (IGF2) mRNA-binding protein 1 (IGF2BP1) mediates lipopolysaccharide (LPS)-induced NF kappa B activation and pro-inflammatory cytokines production in human macrophages. Recent studies have identified a novel IGF2BP1-binding LncRNA LIN28B-AS1. In the present study we show that LPS induced LIN28B-AS1-IGF2BP1 association in THP-1 macrophages, required for LPS-induced IGF2BP1-p65-p52 association and NF kappa B activation. LIN28B-AS1 silencing, by targeted shRNAs, potently inhibited LPS-induced activation of NF kappa B, as well as expression and productions of key pro-inflammatory cytokines, inducing IL-1 beta, IL-6 and TNF-alpha. Conversely, ectopic overexpression of LIN28B-AS1 in THP-1 macrophages potentiated NF kappa B activation and pro-inflammatory cytokines production by LPS. Significantly, LIN28B-AS1 shRNA was ineffective on LPS-induced pro-inflammatory responses in IGF2BP1-knockout THP-1 macrophages. In ex vivo cultured primary human peripheral blood mononuclear cells (PBMCs), LPS-induced IL-1 beta expression and production were attenuated by LIN28B-AS1 shRNA, but augmented with forced LIN28B-AS1 overexpression. Collectively, we show that LIN28B-AS1, binding to IGF2BP1, is required for LPS-induced NF kappa B activation and pro-inflammatory responses in human macrophages. (C) 2019 Elsevier Inc. All rights reserved.