STAT 4 activation by leukemia inhibitory factor confers a therapeutic effect on intestinal inflammation

Abstract

T helper 17 (Th17)‐cell differentiation triggered by interleukin‐6 (IL‐6) via STAT3 activation promotes inflammation in inflammatory bowel disease (IBD) patients. However, leukemia inhibitory factor (LIF), an IL‐6 family cytokine, restricts inflammation by blocking Th17‐cell differentiation via an unknown mechanism. Here, 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 Il17a/Il17f 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, serves as a potential therapy for IBD.

Leukaemia Inhibitory Factor (LIF) Inhibits Cancer Stem Cells Tumorigenic Properties through Hippo Kinases Activation in Gastric Cancer

“…The use of LIF in vivo is however questionable due to its highly pleiotropic aspect. Several in vivo attempts can be found in the literature in which LIF injection or overexpression via implantation of LIF-producing cells in mouse models can promote anti-inflammatory signalling through IL-12 [ 39 ], suppress type 2 immunity in muscular dystrophic mouse model [ 40 ] and inhibit Th17 response in inflamed colon of inflammatory bowel disease models [ 41 ]. In addition, the commercial human LIF Emfilermin TM was used in a phase II clinical trial for the prevention of chemotherapy-induced peripheral neuropathy [ 42 ].…”

LIF is essential for ISC function and protects against radiation-induced gastrointestinal syndrome

“…A recent study reported that LIF plays a protective role in mouse experimental colitis models 37 . Under the colitis condition, microbiota dysregulation induces LIF secretion by IECs.…”

Cynaropicrin Shows Antitumor Progression Potential in Colorectal Cancer through Mediation of the LIFR/STATs Axis

“…A positive feedback loop involving LIF, LIFR, and STAT4 drives sustained IL-6 transcription. In laminar propria lymphocytes of in ammatory bowel disease patients, LIF-activated STAT4 inhibits activation of the STAT3-dependent Il17a/Il17f promoter, while in intestinal epithelial cells, LIF bypasses abnormally low STAT4 levels and induces YAP gene expression by activating STAT3 (22). Therefore, our attempt to investigate the interaction between STAT3 and STAT4 proteins in CRC was meaningful.…”

“…After activation by LIF/LIFR, STAT3 can not only be activated to form a homodimer, but also to form a heterodimer with STAT4 (22). We assessed the in uence of cynaropicrin on the formation of STAT3 dimer, and the results of Co-Immunoprecipitation (Co-IP) using antibodies directed against STAT3 and STAT4 are show in Figures 5A and 5B.…”