STAT4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation [RNA-Seq]

We report that microbiota dysregulation promotes LIF secretion by intestinal epithelial cells (IECs) in a mouse colitis model. LIF greatly activates STAT4 phosphorylation on multiple SPXX elements within the C-terminal transcription regulation domain. STAT4 and STAT3 act reciprocally on both canonical cis-inducible elements (SIEs) and noncanonical “AGG” elements at different loci. In lamina propria lymphocytes (LPLs), STAT4 activation by LIF blocks STAT3-dependent Il-17a/Il-17f promoter activation, whereas in IECs, LIF bypasses the extraordinarily low level of STAT4 to induce YAP gene expression via STAT3 activation. In addition, we found that the administration of LIF is sufficient to restore microbiome homeostasis. Thus, LIF effectively inhibits Th17 accumulation and promotes repair of damaged intestinal epithelium in inflamed colon, and serves as a potential therapy for IBD. Overall design: mRNA profiles in intestinal epithelial cells of wild type (WT) and Stat4-/- mice were generated by deep sequencing, in duplicate, using Illumina-HiSeq2500/4000.