Interleukin-18 Induces Acute Biphasic Reduction in the Levels of Circulating Leukocytes in Mice

Hosohara, Katsushi; Ueda, Hiroyuki; Kashiwamura, Shin-ichiro; Yano, Teruo; Ogura, Takeharu; Marukawa, Seishiro; Okamura, Haruki

doi:10.1128/cdli.9.4.777-783.2002

Cited by 15 publications

(14 citation statements)

References 34 publications

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“…Increased survival is accompanied by decreased levels of IFN-g and MIP-2 in anti-IL-18-treated animals challenged with E. coli LPS, whereas IFN-g and TNF-a concentrations are decreased in treated mice challenged with S. typhimurium. This is consistent with a finding that injections of IL-18 into mice result in profound neutropenia [87]. In mice primed with heatkilled P. acnes, a neutralizing antibody to IL-18 completely prevented LPS-induced hepatic damage, which was associated with reduced IFN-g, TNF-a, and Fas ligand levels, whereas a neutralizing antibody to IL-12 had no effect [88].…”

Section: Role Of Il-18 In Sepsissupporting

confidence: 90%

Interleukin‐18 and Host Defense against Infection

Dinarello¹,

Fantuzzi²

2003

J INFECT DIS

268

214

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Interferon (IFN)-gamma-inducing factor was previously termed interleukin (IL)-18. Although IL-12 is also an IFN-gamma-inducing factor, the activity of IL-18 (but not IL-12) in models of sepsis and death is dependent on the intracellular cysteine protease IL-1beta converting enzyme (caspase-1). Caspase-1 is required for cleavage of the inactive precursor form of IL-18 into an active cytokine, and caspase-1-deficient mice are resistant to lethal endotoxemia. The absence of IFN-gamma (but not IL-1beta) in caspase-1-deficient mice is responsible for this resistance. However, the role of IFN-gamma in murine defense against gram-negative infection is inconsistent. Mice deficient in IFN-gamma are not resistant to lethal endotoxemia but are resistant when treated with neutralizing antibodies to IL-18 and challenged with a lethal injection of some endotoxins. Anti-IL-18 treatment also reduces neutrophil accumulation in liver and lungs. Neutralizing IL-18 with the IL-18 binding protein protects mice against endotoxin- and ischemia-induced hepatic damage. Thus, blockade of IL-18 appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.

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Section: Role Of Il-18 In Sepsissupporting

confidence: 90%

Interleukin‐18 and Host Defense against Infection

Dinarello¹,

Fantuzzi²

2003

J INFECT DIS

268

214

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“…We previously found that a single administration of IL-18 induced NO in peripheral blood in mice (20). The present study shows that plasma NO metabolites, as well as pancreatic iNOS gene expression, were significantly increased after the initiation of AP and that these levels were significantly lower in IL-18 KO than in WT mice.…”

Section: Discussionmentioning

confidence: 48%

“…Upregulation of natural killer cell-mediated cytotoxicity (17), induction of Fas ligand (18), and development of type 1 T-helper (Th1) cells (19) are the first major actions. Additionally, our recent study showed that injection of IL-18 as a bolus into the peritoneal cavity of mice dramatically increased nitric oxide (NO) in peripheral blood, reaching a peak at 4 h, then decreasing to a supranormal level by 24 h (20). NO is a key mediator in modulating microcirculatory change and…”

Section: Introductionmentioning

confidence: 98%

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

Ueno¹,

Kashiwamura

Ueda

et al. 2005

Shock

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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.

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“…On the one hand IL-18 leads to release of TNF alpha, IL-6, and other chemokines, but on the other hand it increases NO level in peripheral blood, as was observed in experimental study [38]. Some studies show that NO may have a protective effect by increasing pancreatic microvascular blood flow [39,40].…”

Section: Discussionmentioning

confidence: 91%