Differential Regulation of Systemic Il-18 and Il-12 Release During Postoperative Sepsis: High Serum Il-18 as an Early Predictive Indicator of Lethal Outcome

Emmanuilidis, Klaus; Weighardt, Heike; Matevossian, Edouard; Heidecke, Claus–Dieter; Ulm, Kurt; Bartels, H.; Siewert, J. R.; Holzmann, Bernhard

doi:10.1097/00024382-200210000-00002

Cited by 76 publications

(51 citation statements)

References 23 publications

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“…Although anti-MIF pretreatment did not result in significant decreases in systemic IL-6 levels in the present study, it is still possible that IL-6 may be blocked locally in the heart, preventing cardiodysfunction in this manner. Interestingly, systemic IL-12 levels were significantly decreased during the 12 h after burn injury, which parallel decreases in IL-12 reported in postsurgical sepsis patients (21). Decreases in IL-12 have been postulated to be involved in sepsis-induced immune energy in animal models and humans (39,46,54).…”

Section: Discussionsupporting

confidence: 58%

Macrophage migration inhibitory factor mediates late cardiac dysfunction after burn injury

Willis¹,

Carlson²,

DiMaio

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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Section: Discussionsupporting

confidence: 58%

Macrophage migration inhibitory factor mediates late cardiac dysfunction after burn injury

Willis¹,

Carlson²,

DiMaio

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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“…However, cases of prerenal AKI would "dilute" the association between urine IL-18 and AKI; thus, the reported results are conservative estimates of the association. Second, there may be a systemic production of IL-18 as suggested by some authors (25). However, the lack of an effect of sepsis on urine IL-18 and very low concentrations of IL-18 in control subjects with sepsis argues against a major systemic contribution of IL-18 production and confirms that kidneys may be the major source of IL-18 production.…”

Section: Discussionmentioning

confidence: 80%

Urine IL-18 Is an Early Diagnostic Marker for Acute Kidney Injury and Predicts Mortality in the Intensive Care Unit

Parikh

Abraham

Ancukiewicz

et al. 2005

Journal of the American Society of Nephrology

502

328

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Serum creatinine is not an ideal marker of renal function in patients with acute kidney injury (AKI). Previous studies demonstrated that urinary IL-18 is increased in human AKI. Thus, whether urine IL-18 is an early diagnostic marker of AKI was investigated. A nested case-control study was performed within the Acute Respiratory Distress Syndrome (ARDS) Network trial. AKI was defined as an increase in serum creatinine by at least 50% within the first 6 d of ARDS study enrollment. A total of 400 urine specimens that were collected on study days 0, 1, and 3 of the ARDS trial were available from 52 case patients and 86 control patients. The data were analyzed in a cross-sectional manner and according to the time before development of AKI. The median urine IL-18 levels were significantly different at 24 and 48 h before AKI in case patients as compared with control patients. On multivariable analysis, urine IL-18 values predicted development of AKI 24 and 48 h later after adjustment for demographics, sepsis, Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) III score, serum creatinine, and urine output. Urine IL-18 levels of >100 pg/ml are associated with increased odds of AKI of 6.5 (95% confidence interval 2.1 to 20.4) in the next 24 h. On diagnostic performance testing, urine IL-18 demonstrates an area under the receiver operating characteristic curve of 73% to predict AKI in the next 24 h. The urine IL-18 values were also significantly different between survivors and nonsurvivors (P < 0.05), and on multivariable analysis, the urine IL-18 value on day 0 is an independent predictor of mortality. Urinary IL-18 levels can be used for the early diagnosis of AKI. Urine IL-18 levels also predict the mortality of patients who have ARDS and are in the intensive care unit. A cute kidney injury (AKI) is typically diagnosed by a progressive rise in serum creatinine over several days, which may or may not be associated with oliguria. Changes in serum creatinine lag several days behind actual changes in GFR, and the alterations in serum creatinine are not particularly sensitive or specific for small changes in GFR. The detection of a reliable biomarker for early diagnosis of AKI would assist in facilitating early intervention, evaluating the effectiveness of the therapeutic intervention, and guiding pharmaceutical development (1,2).Using caspase-1-deficient mice and anti-IL-18 antiserum, we demonstrated that IL-18 mediates ischemic acute tubular necrosis in mice (3,4). These preclinical observations suggested that IL-18 in the urine has the potential to serve as a biomarker for AKI in humans. To evaluate this hypothesis, we performed a cross-sectional study in humans and measured urine IL-18 in patients with established AKI and other kidney diseases (5). Urine IL-18 levels were significantly increased in patients with AKI compared with prerenal azotemia, urinary tract infection, chronic renal insufficiency, and nephrotic syndrome. Urinary IL-18 levels had sensitivity and specificity of Ͼ90% for diagnosis of es...

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“…IL-18 has recently been implicated in the pathogenesis of several inflammatory diseases (26) and severe sepsis (11,18,23). The mechanisms by which IL-18 promotes inflammatory responses may be related to its priming of the PMN oxidative burst.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-18 Primes the Oxidative Burst of Neutrophils in Response to Formyl-Peptides: Role of Cytochrome b558 Translocation and N-Formyl Peptide Receptor Endocytosis

Elbim

Guichard

Dang

et al. 2005

Clin Vaccine Immunol

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Using flow cytometry, we observed that interleukin-18 (IL-18) primed human neutrophils (PMNs) in whole blood to produce superoxide anion (O 2°؊ ) in response to N-formyl peptide (fMLP) stimulation, whereas IL-18 alone had no significant effect. In contrast to tumor necrosis factor alpha (TNF-␣), which is a cytokine known to strongly prime O 2°؊ production, IL-18 did not induce either p47 phox phosphorylation or its translocation from the cytosol to the plasma membrane. However, IL-18 increased PMN degranulation, as shown by increased levels of cytochrome b558 and CD11b expression at the PMN surface. Moreover, addition of IL-18 to whole blood for 45 min reduced the ability of PMNs to bind to fMLP, suggesting endocytosis of fMLP receptors, as visualized by confocal microscopy. 2,3-Butanedione 2-monoxime, which inhibits endosomal recycling of plasma membrane components back to the cell surface, concomitantly accentuated the diminution of fMLP binding at the PMN surface and increased IL-18 priming of O 2°؊ production by PMNs in response to fMLP. This suggests that fMLP receptor endocytosis could account, at least in part, for the priming of O 2°؊ production. In addition, genistein, a tyrosine kinase inhibitor, and SB203580, a p38 mitogen-activated protein kinase (p38MAPK) inhibitor, completely reversed the decreased level of fMLP binding and increased the level of CD11b expression after IL-18 treatment. Flow cytometric analysis of intact PMNs in whole blood showed that IL-18 increased p38MAPK phosphorylation and tyrosine phosphorylation. In particular, IL-18 induced phosphorylation of focal adhesion kinase (p125 FAK ), which has been implicated in cytoskeleton reorganization. Taken together, our findings suggest several mechanisms that are likely to regulate cytokine-induced priming of the oxidative burst in PMNs in their blood environment.

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Differential Regulation of Systemic Il-18 and Il-12 Release During Postoperative Sepsis: High Serum Il-18 as an Early Predictive Indicator of Lethal Outcome

Cited by 76 publications

References 23 publications

Macrophage migration inhibitory factor mediates late cardiac dysfunction after burn injury

Macrophage migration inhibitory factor mediates late cardiac dysfunction after burn injury

Urine IL-18 Is an Early Diagnostic Marker for Acute Kidney Injury and Predicts Mortality in the Intensive Care Unit

Interleukin-18 Primes the Oxidative Burst of Neutrophils in Response to Formyl-Peptides: Role of Cytochrome b558 Translocation and N-Formyl Peptide Receptor Endocytosis

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