MiR-140/BDNF axis regulates normal human astrocyte proliferation and LPS-induced IL-6 and TNF-α secretion.

Abstract

Reactive astrocyte proliferation after spinal cord injury (SCI) contributes to glial scar formation that impedes axonal regeneration. The mechanisms underlying astrocyte proliferation upon injury remain partially understood. MicroRNAs (miRNAs) function as a major class of post-transcriptional gene expression regulators that participate in many biological processes. In this study, we focused on the functional role of miR-140 in normal human astrocyte (NHA) cell proliferation. Ectopic miR-140 expression significantly inhibited NHA cell viability and proliferation; miR-140 inhibition exerted the opposite function. Commonly, miRNAs exert functions through targeting downstream genes to inhibit their expression. In the present study, brain-derived neurotrophic factor (BDNF), a regulator of astrocyte proliferation and differentiation, confirmed as a direct target of miR-140 in NHA. Through binding to the 3'UTR of BDNF, miR-140 inhibited BDNF expression. BDNF overexpression significantly promoted NHA cell viability and proliferation; the regulatory effect of miR-140/BDNF on NHA proliferation was mediated by PI3K/AKT pathway. Moreover, we evaluated the functional role of miR-140 in Lipopolysaccharide (LPS)-induced in vitro injury model of astroglial cultures; a significantly up-regulated BDNF, interleukin (IL)-6 and tumor necrosis factor (TNF)-α expression in response to LPS stimulation was observed. After ectopic miR-140 expression, the promotive effect of LPS on BDNF, IL-6 and TGF-α expression was partially restored. Taken together, miR-140/BDNF axis regulates NHA proliferation through PI3K/AKT pathway; miR-140 could inhibit BDNF, IL-6 and TGF-α expression in LPS-induced in vitro injury model. MiR-140/BDNF might serve as a promising target in strategy against reactive astrocyte proliferation after SCI.