IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner

Chikano, Shinji; Sawada, Koji; Shimoyama, Takashi; Kashiwamura, Shin-ichiro; Sugihara, Ayako; Sekikawa, Kenji; Terada, Nobuyuki; Nakanishi, Kenji; Okamura, Haruki

doi:10.1136/gut.47.6.779

Cited by 106 publications

(89 citation statements)

References 43 publications

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“…Two injections of the combination of IL-12 plus IL-18 induced 100% lethality by 48 h after the second injection in ob/ob mice (zero of 10 surviving mice in two separate experiments); in contrast, no lethality was observed in WT mice up to 2 wk posttreatment (10 of 10 surviving mice in two separate experiments). In agreement with previous studies (32,33), administration of a 5-fold-higher dose of IL-12 plus IL-18 resulted in 30% lethality in WT mice over the course of 7 d (two of six surviving mice). As shown in Fig.…”

Section: Resultssupporting

confidence: 79%

“…The effects observed included alterations of liver function and intestinal inflammation (31)(32)(33). These changes were associated with high levels of IFN-␥ and other cytokines.…”

mentioning

confidence: 99%

“…These changes were associated with high levels of IFN-␥ and other cytokines. Neutralization of IFN-␥ or the use of IFN-␥-deficient mice protected from the toxicity of the IL-12 and IL-18 mixture (32,33).In the present study we investigated the effect of dosing mice with two injections of IL-12 plus IL-18 on pancreatic inflammation and the influence of leptin as well as obesity. We demonstrate that obesity associated with leptin deficiency enhances sensitivity to the toxic effects of the IL-12 plus IL-18 combination on the pancreas and that obesity per se rather than leptin deficiency seems to account for the increased severity of AP observed in leptindeficient ob/ob mice.…”

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confidence: 99%

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confidence: 99%

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Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Sennello¹,

Fayad²,

Pini³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Obesity is associated with increased severity of acute pancreatitis (AP). The cytokines IL-18 and IL-12 are elevated in patients with AP, and IL-18 levels are high in obesity. We aimed to develop a pathologically relevant model to study obesity-associated severe AP. Lean WT and obese leptin-deficient ob/ob mice received two injections of IL-12 plus IL-18. Survival, pancreatic inflammation, and biochemical markers of AP were measured. Dosing with IL-12 plus IL-18 induced 100% lethality in ob/ob mice; no lethality was observed in WT mice. Disruption of pancreatic exocrine tissue and acinar cell death as well as serum amylase and lipase levels were significantly higher in ob/ob than in WT mice. Edematous AP developed in WT mice, whereas obese ob/ob mice developed necrotizing AP. Adipose tissue necrosis and saponification were present in cytokine-injected ob/ob but not in WT mice. Severe hypocalcemia and elevated acute-phase response developed in ob/ob mice. The cytokine combination induced high levels of regenerating protein 1 and pancreatitis-associated protein expression in the pancreas of WT but not of ob/ob mice. To differentiate the contribution of obesity to that of leptin deficiency, mice received short-and long-term leptin replacement therapy. Shortterm leptin reconstitution in the absence of major weight loss did not protect ob/ob mice, whereas leptin deficiency in the absence of obesity resulted in a significant reduction in the severity of the pancreatitis. In conclusion, we developed a pathologically relevant model of AP in which obesity per se is associated with increased severity.cytokines ͉ inflammation ͉ obesity ͉ pancreas A cute pancreatitis (AP) is an inflammatory disorder that ranges from interstitial edema to confluent necrosis and hemorrhage. In severe cases, progress to circulatory shock, acute lung injury, renal failure, and eventual death may occur (1). Despite some controversy, numerous studies have demonstrated that obesity is associated with increased risk of the severe form of AP and with development of life-threatening complications (2-8). However, the mechanism by which increased adiposity worsens AP remains unknown.Leptin, a protein mainly produced by adipocytes, is a critical regulator of appetite (9). Leptin exerts important regulatory effects on inflammation (10). In the context of AP, the role of leptin remains controversial. In patients with AP, a correlation between serum leptin and disease severity has been reported by some investigators but not by others (11,12). Although in animal models administration of leptin decreases AP severity (13-16), more severe disease is present in leptin-deficient ob/ob and leptin receptordeficient db/db mice as well as leptin-receptor mutant fa/fa rats (17, 18). However, the differential effect of obesity versus leptin deficiency has not been fully investigated.IL-12 and IL-18 are two proinflammatory cytokines that drive the Th1 cell response, characterized by high levels of IFN-␥ (19). Both cytokines are mainly produced by monocytes/macrophages....

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Section: Resultssupporting

confidence: 79%

“…The effects observed included alterations of liver function and intestinal inflammation (31)(32)(33). These changes were associated with high levels of IFN-␥ and other cytokines.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Sennello¹,

Fayad²,

Pini³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Together, these proinflammatory factors can induce intestinal inflammation in mice [26]. Prior studies have demonstrated conflicting results regarding the production of IL-12 in rats undergoing a NEC-inducing protocol when compared to dam fed controls.…”

Section: Discussionmentioning

confidence: 99%

Unexpected Macrophage Activity Alters the Inflammatory Process in Necrotizing Enterocolitis

Raque¹,

Matheson²,

Connolly³

et al. 2017

J Cytokine Biol

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Objective: Macrophages play a role in clearing bacteria from the gut in the initial stages of necrotizing enterocolitis (NEC). Macrophage Inflammatory Protein-1α (MIP-1α), also known as CCL3, is a chemokine produced by macrophages that enhances the immune response. It acts as both a recruiter of immune cells and a coactivator of other macrophages. Interleukin-12 (IL-12) is a pro-inflammatory chemotactant produced by several types of phagocytic cells such as dendritic cells and neutrophils, but primarily by macrophages. We hypothesized that the pro-inflammatory state associated with NEC pathophysiology would induce increased expression of MIP-1α and IL-12 that would be detectable in serum and intestinal tissue.Methods: Timed pregnant Sprague-Dawley rats were randomized by litter. Controls were delivered vaginally and dam-fed. NEC pup groups were delivered 12 h prematurely via Cesarean section, formula fed, given a single oral dose of lipopolysaccharide, and subjected to intermittent cold and hypoxia as part of a proven NEC rat model protocol. Animals were sacrificed at 0, 12, 24, 48, 72, and 96 h of life and serum and intestinal tissue samples were collected. Samples were analysed via western blot using antibodies with affinity to MIP-1α and IL-12 respectively.Results: Serum and ileal levels of MIP-1 alpha were increased from 48 to 72 h in NEC animals when compared with controls. Serum and ileal IL-12 was downregulated in NEC groups at 12 and 24 h compared to controls. Conclusion:Macrophage function plays an important role in the first 48 h of NEC pathophysiology. Downregulation of IL-12 in the setting of increased MIP-1α expression may represent deranged or inhibited macrophage function in the context of NEC pathogenesis. Further work to elucidate the significance of these findings is warranted.

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Enhanced production of IL-18 in butyrate-treated intestinal epithelium by stimulation of the proximal promoter region

et al. 2002

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Expression of IL‐18 in intestinal epithelial cells (IEC) has been implicated in Th1 cell‐mediated chronic intestinal inflammation and anti‐tumor immunity. However, physiological regulatory factors have not been identified. Besides their effects on proliferation and restitution, immunomodulatory functions have been attributed to short chain fatty acids (SCFA). We investigated the effect of SCFA (butyrate, propionate, acetate) on expression of IL‐18 in IEC in vitro and in vivo. Expression of IL‐18 mRNA and protein in human carcinoma‐derived HT‐29 and Caco‐2 cells was analyzed by reverse transcription‐PCR and Western blot. Transcriptional regulation of IL‐18 gene expression was determined by transient transfection of wild‐type and mutated IL‐18 promoter. Further, in vivo expression of IL‐18 in the intestine from butyrate‐treated and untreated mice was assessed by immunohistochemistry. IL‐18 mRNA and the IL‐18 protein were expressed in IEC, while IL‐18 secretion was not observed. Butyrate and acetate increased intracellular IL‐18 content in a time‐ and dose‐dependent fashion. In contrast to proinflammatory stimuli butyrate potently activated the IL‐18 promoter, indicating that IL‐18 is regulated at the transcriptional level by SCFA. Furthermore, a 108‐bp sequence in the proximal region was identified to be essential for IL‐18 promoter activation by butyrate. As proof of principle butyrate effects were confirmed in vivo by demonstration of increased IL‐18 protein expression in IEC from butyrate‐treated mice. In conclusion, SCFAup‐regulate IL‐18 protein expression in IEC, suggesting a potential regulatory contribution of these luminal constituents to T cell mediated inflammatory and neoplastic intestinal conditions.

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IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner

Cited by 106 publications

References 43 publications

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Interleukin-18, together with interleukin-12, induces severe acute pancreatitis in obese but not in nonobese leptin-deficient mice

Unexpected Macrophage Activity Alters the Inflammatory Process in Necrotizing Enterocolitis

Enhanced production of IL-18 in butyrate-treated intestinal epithelium by stimulation of the proximal promoter region

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