Decreased development of necrotizing enterocolitis in IL-18-deficient mice

Abstract

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease predominantly of prematurely born infants, characterized in its severest from by extensive hemorrhagic inflammatory necrosis of the distal ileum and proximal colon. Proinflammatory cytokines have been implicated in the development of NEC, and we have previously shown that IL-18 is significantly elevated in the well-established neonatal rat model of NEC. To determine whether IL-18 contributes to intestinal pathology in NEC, we subjected IL-18 knockout mice to the protocol used to develop experimental NEC in newborn rats. Newborn B6.129P2-Il18(tm1Aki)/J (NEC IL-18(-/-)) and wild-type (NEC WT) mice were hand fed every 3 h with cow's milk-based formula and exposed to asphyxia and cold stress twice daily. After 72 h, animals were killed and distal ileum and liver were removed. Disease development was determined via histological changes in the ileum as scored by a blinded evaluator. The number of TNF-alpha-, IL-12-, and IL-1beta-positive cells and macrophages were determined in both ileum and liver via immunohistology. IkappaB-alpha and IkappaB-beta were determined from protein extracts from both ileum and liver using Western blot analysis. The incidence and severity of NEC was significantly reduced in NEC IL-18(-/-) mice compared with NEC WT. Furthermore, mean ileal macrophages and hepatic IL-1beta were significantly reduced in IL-18(-/-) mice subjected to the NEC protocol. There were no statistically significant changes in Kupffer cells, hepatic TNF-alpha, ileal IL-1beta, or IL-12. IkappaB-alpha and IkappaB-beta were significantly increased in NEC IL-18(-/-) mice ileum and liver, respectively. These results confirm that IL-18 plays a crucial role in experimental NEC pathogenesis.

Inflammatory response in a rat model of gastroschisis is associated with an increase of NF-kappaB

“…Intestinal inflammation has also been associated with the increase of NF-kappaB, which has been demonstrated to play a key role both in inflammatory bowel disease and gastroschisis (23)(24)(25)(26). We also found elevation of NFkappaB levels both in the intestine and liver of fetuses with gastroschisis (P < 0.05).…”

Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis

“…However, it has been suggested that bacterial endotoxin can trigger an innate immune response characterized by cytokine production (60). Our and other laboratories have shown that proinflammatory cytokines are important factors contributing to NEC pathogenesis (25,27,58). Clinical studies have reported increased serum levels of TNF-␣ and IL-6 in NEC patients (58).…”

Pomegranate seed oil reduces intestinal damage in a rat model of necrotizing enterocolitis

“…We (26,27) and others (20,41,53) have shown the dysregulation of inflammatory cytokines in the intestinal mucosa during NEC pathogenesis. Par-ticularly, interleukin (IL)-6, IL-8, IL-12, IL-18, and tumor necrosis factor-␣ (TNF-␣) have an important role and a diagnostic value in sepsis and in NEC (9,26,45).…”