Role of Interleukin 18 in Nitric Oxide Production and Pancreatic Damage During Acute Pancreatitis

Abstract

The release of the immunomodulator, interleukin 18 (IL-18) into sera early in acute pancreatitis (AP) corresponds to disease severity. IL-18 induces nitric oxide (NO), which is involved in the pathophysiology of pancreatitis. The objective of this study was to clarify the role of IL-18 in pathogenesis and NO production during early AP using recombinant mouse (rm) IL-18 protein and IL-18 gene knockout (KO) mice. After pretreatment with phosphate-buffered saline or rmIL-18, wild-type (WT) or KO mice were injected intraperitoneally with phosphate-buffered saline (sham) or cerulein (AP) hourly for 3 h. Blood, pancreas, spleen, and liver were collected until 24 h after the first dose. Main outcome measures were serum IL-18, amylase and lipase levels, histological evaluation of the pancreas with parenchyma vacuolization of acinar cells, mRNA expression of inducible NO synthase (iNOS) in the pancreas, and spleen, liver, and plasma NO metabolite level. Serum IL-18 was significantly increased immediately after induction of AP in WT mice. Serum amylase, lipase, and the numbers of acinar cells with parenchyma vacuolization were significantly higher in the group AP/KO than in the group AP/WT, but these parameters were improved by dose-dependent pretreatment with rmIL-18 administration in both groups. Pancreatic iNOS gene expression and plasma NO metabolites were significantly increased by 6 h after the initiation of AP, but were significantly lower in the group AP/KO than in the AP/WT mice. Pretreatment with rmIL-18 also significantly increased these levels in both groups. Splenic and hepatic iNOS expression was not changed after the initiation of AP in WT mice, whereas pretreatment with rmIL-18 also increased these levels. Administration of aminoguanidine, a selective iNOS inhibitor, before AP induction abolished the protective effect of pretreatment with rmIL-18 on pancreatic injury. IL-18 appears to protect the pancreas during early induced-induced AP in mice, probably through induction of NO release from an iNOS source. IL-18 may be a target for new AP therapeutics.

Endogenous interleukin 18 regulates testicular germ cell apoptosis during endotoxemia

“…Therefore, up-regulation of FAS and FASL by IL18 may influence BID activation. IL18 was also required for iNOS IL18 regulates testicular germ cell apoptosis induction, in accordance with the findings of a previous study (Ueno et al 2005). The upregulation of iNOS increases cellular NO levels, which leads to the breakdown of mitochondrial membrane potential and caspase-9 activation (Chan et al 2005).…”

Role of endogenous IL‐18 in the lung during endotoxin‐induced systemic inflammation

“…8 The present study also showed that endogenous IL-18 induced accumulation of neutrophils, iNOS expression, and oxidative stress in the lung. These results are consistent with previously reported evidence; Hesslinger et al showed that iNOS induced neutrophil accumulation and pulmonary edema.…”

“…7 We also reported that endogenous IL-18 induced iNOS expression during acute pancreatitis in mice. 8 These findings suggest that endogenous IL-18 may relate to accumulating neutrophils and their apoptosis, as well as oxidative stress in acute lung injury.…”

Delayed Production of IL-18 in Lungs and Pancreas of Rats with Acute Pancreatitis

“…These cytokines are expressed mainly during the early stages of the disease in serum, pancreas or lungs. Consequently, they may contribute to the disease course only over a brief period of time [15]. In contrast to the profile of these commonly described cytokines, IL-18 expression is delayed.…”