IFN-γ Protects Cerulein-Induced Acute Pancreatitis by Repressing NF-κB Activation

Abstract

We explored the pathophysiological roles of IFN-γ in cerulein-induced acute pancreatitis. In wild-type (WT) mice, cerulein injection caused acute pancreatitis as evidenced by increased serum amylase levels and pathological changes such as interstitial edema, vacuolization, acinar cell necrosis, and neutrophil infiltration in pancreas. Concomitantly, cerulein treatment augmented intrapancreatic gene expression of TNF-α, KC/CXCL1, MIP-2/CXCL2, cyclooxygenase-2 (COX-2), and IFN-γ in WT mice. In situ hybridization combined with immunofluorescence analyses demonstrated that infiltrating neutrophils expressed IFN-γ mRNA. Unexpectedly, IFN-γ−/− mice exhibited exacerbated cerulein-induced pancreatic injury, with enhanced neutrophil recruitment. Moreover, intrapancreatic gene expression of TNF-α, KC/CXCL1, MIP-2/CXCL2, and COX-2 were significantly exaggerated in IFN-γ−/− mice, compared with WT mice. Cerulein activated NF-κB, an indispensable transcription factor for gene transcription of TNF-α, KC/CXCL1, MIP-2/CXCL2, and COX-2, in pancreas of cerulein-treated WT mice as evidenced by the increases in nuclear amount and DNA-binding activity of NF-κB p65. In comparison with WT mice, IFN-γ−/− mice exhibited exaggerated and prolonged NF-κB activation, probably due to reduced acetylation of Stat1, a main signal transducer of IFN-γ, because acetylated Stat1 can inhibit NF-κB activation. Indeed, IFN-γ acetylated Stat1 and reciprocally reduced NF-κB activation and COX-2 expression in neutrophils. Finally, even when administered 4 h after the first cerulein injection, IFN-γ remarkably attenuated acute pancreatitis in both WT and IFN-γ−/− mice, with reduced NF-κB activation and COX-2 expression. Thus, IFN-γ can have anti-inflammatory effects on acute pancreatitis by depressing the proinflammatory consequences of NF-κB activation.

Phosphorylation–acetylation switch in the regulation of STAT1 signaling

“…This observation is consistent with dynamic interactions of STAT1 with HATs and HDACs. Our observations have been confirmed in other systems, including an in vivo mouse model of pancreatitis [23,58,68,69]. Of note, excessive immune stimulation is linked to pancreatic tumorigenesis [70,71].…”

“…STAT1 acetylation impairs STAT1 itself as well as NF-B [35,68,75]. These proteins are key mediators of the inflammatory response and a multitude of factors regulate this process.…”

“…with thyroid and pancreatic cancers [70,71,115]. Interestingly, STAT1 expression can be down-regulated in pancreatic cancers, head and neck tumors, and melanomas [35,72,73] and IFN induces acetylation of STAT1 counteracting pancreatitis [68] . HDACi-induced STAT1 expression and acetylation might thus contribute to the correction of chronic inflammatory processes contributing to cancer development [116][117][118].…”

Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

“…22 Each fraction was subjected to western blotting using anti-NF-kB p65 pAbs. In parallel, nuclear fractions were analyzed by using an EZ-Detect Transcription Factor kit (Pierce) to determine NFkB p65 protein bound to the corresponding cis element, according to the manufacturer's instructions.…”

Emodin diminishes immune stress in rats with severe acute pancreatitis

“…Cyclooxygenase (COX), has two isoforms: COX-1 and COX-2, is a key enzyme in the synthesis of prostaglandins from arachidonic acid [20]. COX-2, induced by mitogens, proinflammatory cytokines, growth factors, and tumor promoters, is a crucial and central mediator in the development and severity of acute pancreatitis [21]. Peroxisome Proliferator-Activated Receptors (PPARs) are ligand activated transcription factors, which play a modulatory role in the inflammatory response of different organs, belonging to the nuclear receptor superfamily.…”