Interferon-ß alleviates sepsis by SIRT1-mediated blockage of endothelial glycocalyx shedding.

Sepsis is a life-threatening multi-organ dysfunction with high mortality caused by the body's improper response to microbial infection. No new effective therapy has emerged that can adequately treat patients with sepsis. We previously demonstrated that interferon-ß (IFN-ß) protects against sepsis via sirtuin 1-(SIRT1)-mediated immunosuppression. Another study also reported its significant protective effect against acute respiratory distress syndrome, a complication of severe sepsis, in human patients. However, the IFN-ß effect cannot solely be explained by SIRT1-mediated immunosuppression, since sepsis induces immunosuppression in patients. Here, we show that IFN-ß, in combination with nicotinamide riboside (NR), alleviates sepsis by blocking endothelial damage via SIRT1 activation. IFN-ß plus NR protected against cecal ligation puncture-(CLP)-induced sepsis in wild-type mice, but not in endothelial cell-specific Sirt1 knockout (EC-Sirt1 KO) mice. IFN-ß upregulated SIRT1 protein expression in endothelial cells in a protein synthesisindependent manner. IFN-ß plus NR reduced the CLP-induced increase in in vivo endothelial permeability in wild-type, but not EC-Sirt1 KO mice. IFN-ß plus NR suppressed lipopolysaccharide-induced up-regulation of heparinase 1, but the effect was abolished by Sirt1 knockdown in endothelial cells. Our results suggest that IFN-ß plus NR protects against endothelial damage during sepsis via activation of the SIRT1/heparinase 1 pathway. [BMB Reports 2023; 56(5): 314-319].

Changes in the phosphorylation of nucleotide metabolism­associated proteins by leukemia inhibitory factor in mouse embryonic stem cells.

Leukemia inhibitory factor (LIF) is a stem cell growth factor that maintains self­renewal of mouse embryonic stem cells (mESCs). LIF is a cytokine in the interleukin­6 family and signals via the common receptor subunit gp130 and ligand­specific LIF receptor. LIF causes heterodimerization of the LIF receptor and gp130, activating the Janus kinase/STAT and MAPK pathways, resulting in changes in protein phosphorylation. The present study profiled LIF­mediated protein phosphorylation changes in mESCs via proteomic analysis. mESCs treated in the presence or absence of LIF were analyzed via two­dimensional differential in­gel electrophoresis and protein and phosphoprotein staining. Protein identification was performed by matrix­assisted laser desorption/ionization­time of flight mass spectrophotometry. Increased phosphorylation of 16 proteins and decreased phosphorylation of 34 proteins in response to LIF treatment was detected. Gene Ontology terms enriched in these proteins included 'organonitrogen compound metabolic process', 'regulation of mRNA splicing via spliceosome' and 'nucleotide metabolic process'. The present results revealed that LIF modulated phosphorylation levels of nucleotide metabolism­associated proteins, thus providing insight into the mechanism underlying LIF action in mESCs.