Stat2 loss disrupts damage signalling and is protective in acute pancreatitis

Abstract

The severity of sterile inflammation, as seen in acute pancreatitis, is determined by damage‐sensing receptors, signalling cascades and cytokine production. Stat2 is a type I interferon signalling mediator that also has interferon‐independent roles in murine lipopolysaccharide‐induced NF‐κB‐mediated sepsis. However, its role in sterile inflammation is unknown. We hypothesised that Stat2 determines the severity of non‐infective inflammation in the pancreas. Wild type (WT) and Stat2−/− mice were injected i.p. with caerulein or l‐arginine. Specific cytokine‐blocking antibodies were used in some experiments. Pancreata and blood were harvested 1 and 24 h after the final dose of caerulein and up to 96 h post l‐arginine. Whole‐tissue phosphoproteomic changes were assessed using label‐free mass spectrometry. Tissue‐specific Stat2 effects were studied in WT/Stat2−/− bone marrow chimera and using Cre‐lox recombination to delete Stat2 in pancreatic and duodenal homeobox 1 (Pdx1)‐expressing cells. Stat2−/− mice were protected from caerulein‐ and l‐arginine‐induced pancreatitis. Protection was independent of type I interferon signalling. Stat2−/− mice had lower cytokine levels, including TNF‐α and IL‐10, and reduced NF‐κB nuclear localisation in pancreatic tissue compared with WT. Inhibition of TNF‐α improved (inhibition of IL‐10 worsened) caerulein‐induced pancreatitis in WT but not Stat2−/− mice. Phosphoproteomics showed downregulation of MAPK mediators but accumulation of Ser412‐phosphorylated Tak1. Stat2 deletion in Pdx1‐expressing acinar cells (Stat2flox/Pdx1‐cre) reduced pancreatic TNF‐α expression, but not histological injury or serum amylase. WT/Stat2−/− bone marrow chimera mice were protected from pancreatitis irrespective of host or recipient genotype. Stat2 loss results in disrupted signalling in pancreatitis, upstream of NF‐κB in non‐acinar and/or bone marrow‐derived cells. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Andrographolide protect against lipopolysacharides induced vascular endothelium dysfunction by abrogation of oxidative stress and chronic inflammation in Sprague–Dawley rats

“…[ 21 ] TNF‐α is recognized as one of the primary elements within pro‐inflammatory cytokines, directly causing inflammatory effects on the vascular endothelium of blood vessels. [ 22 ] Furthermore, recent studies have indicated that the pro‐inflammatory cytokine IL‐1 within the vascular system acts as a significant mediator closely associated with vascular dysfunction and CVD. Consequently, we assessed the levels of TNF‐α and IL‐1 to better understand the mechanism responsible for the vascular protection offered by AG.…”