Level and Value of Interleukin-18 After Acute Ischemic Stroke

Yuen, Chun-Man; Chiu, Chih-Yi; Chang, Li-Teh; Liou, Chia‐Wei; Lu, Cheng-Hsien; Youssef, Ali A.; Yip, Hon‐Kan

doi:10.1253/circj.71.1691

Cited by 47 publications

(56 citation statements)

References 31 publications

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“…the correlation of IL-18 levels with the patient's cognitive impairment and disability severity, further supports the concept that IL-18 may contribute to the long-term outcome of TBI. Indeed, a correlation between the circulating levels of IL-18 and disease outcome has been previously described also in stroke [30,31] and AD [18,29], both brain diseases characterized by increased brain levels of IL-18, confirming the possible link between the brain and blood increase of this cytokine in CNS pathological conditions. Notably, in AD patients the correlation between peripheral IL-18 amounts (evaluated both at cellular and at serum levels) and severity of disease outcome was assessed in terms of the decline of cognitive functions [18], further validating the result of the present study.…”

Section: Discussionmentioning

confidence: 62%

Increased Levels of Serum IL-18 Are Associated with the Long-Term Outcome of Severe Traumatic Brain Injury

Ciaramella

Vedova

Salani

et al. 2013

Neuroimmunomodulation

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Objective: A long-lasting neuroinflammatory cascade may lead to the progression of brain damage, favoring neurodegeneration and cognitive impairment in patients with traumatic brain injury (TBI), but the potential mechanisms underlying this sequence of events remain elusive. Here we aimed to evaluate the impact of interleukin (IL)-18, a proinflammatory cytokine elevated in post-acute head injury and associated with neurodegeneration, on the long-term outcome of patients with chronic TBI. Methods: The serum content of IL-18 was evaluated in 16 patients with severe TBI, during their rehabilitation phase, and in a matched group of 16 healthy controls. The disability of the enrolled patients was evaluated by means of the Glasgow Outcome Scale, Levels of Cognitive Functioning, and the Disability Rating Scale. Results: The circulating levels of IL-18 were significantly increased in chronic TBI patients, as compared to healthy subjects, and correlated with the patients' cognitive impairment and disability severity. Conclusions: IL-18 may contribute to the long-term outcome and neurodegeneration in TBI patients. Even though further studies are needed to understand the molecular mechanisms underlying the effects of IL-18 on TBI progression and its associated drop in cognitive function, a possible role of this cytokine as a therapeutic target in TBI can be envisaged.

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Section: Discussionmentioning

confidence: 62%

Increased Levels of Serum IL-18 Are Associated with the Long-Term Outcome of Severe Traumatic Brain Injury

Ciaramella

Vedova

Salani

et al. 2013

Neuroimmunomodulation

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“…For example, although it has been reported that systemic IL-18 concentrations in vivo vary widely between 200 and 900 pg/ml in various pathophysiological conditions (19,52), we used 5 ng/ml IL-18 to study the response pathways underlying the induction of EMMPRIN and MMP-9. This concentration is somewhat high but is in line with levels (1-100 ng/ml) used in previous studies (6 -9, 50).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Sp1 signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-κB activation

Reddy

Prabhu²,

Mummidi

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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and the extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN) stimulate the expression of proinflammatory cytokines and MMPs and are elevated in myocardial hypertrophy, remodeling, and failure. Here, we report several novel findings in primary cardiomyocytes treated with IL-18. First, IL-18 activated multiple transcription factors, including NF-B (p50 and p65), activator protein (AP)-1 (cFos, cJun, and JunD), GATA, CCAAT/enhancer-binding protein, myocyte-specific enhancerbinding factor, interferon regulatory factor-1, p53, and specific protein (Sp)-1. Second, IL-18 induced EMMPRIN expression via myeloid differentiation primary response gene 88/IL-1 receptor-associated kinase/TNF receptor-associated factor-6/JNK-dependent Sp1 activation. Third, IL-18 induced a number of MMP genes, particularly MMP-9, at a rapid rate as well as tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-3 at a slower rate. Finally, the IL-18 induction of MMP-9 was mediated in part via EMMPRIN and through JNK-and ERK-dependent AP-1 activation and p38 MAPK-dependent NF-B activation. These results suggest that the elevated expression of IL-18 during myocardial injury and inflammation may favor EMMPRIN and MMP induction and extracellular matrix degradation. Therefore, targeting IL-18 or its signaling pathways may be of potential therapeutic benefit in adverse remodeling. myocardial remodeling; extracellular matrix; extracellular matrix metalloproteinase inducer; matrix metalloproteinase; tissue inhibitor of metalloproteinase; c-Jun NH2 terminal kinase; specific protein-1; activator protein-1; nuclear factor-B

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“…Circulating IL-18 levels have been shown to be independent predictors of coronary events in humans, with increased basal levels of IL-18 observed in individuals who later developed coronary events (7). Increased circulating IL-18 levels have also been measured during heart failure as well as in stroke patients (8,9). IL-18 signals via the IL-18 receptor, a heterodimer consisting of a ligand binding ␣-subunit and a signal-transducing ␤-subunit (10,11).…”

mentioning

confidence: 99%

Neutralization of Interleukin-18 Ameliorates Ischemia/Reperfusion-induced Myocardial Injury

Venkatachalam

Prabhu

Reddy

et al. 2009

Journal of Biological Chemistry

114

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For both men and women, ischemic heart disease is one of the leading causes of death in the United States today, and its pathobiology has been attributed to many factors, including proinflammatory cytokines. Interleukin (IL) 2 -18 is a pleiotropic cytokine belonging to the IL-1 family (1-5), whose expression is up-regulated in numerous immune, infectious, and inflammatory conditions (1-5), which may further amplify the inflammatory cascade by inducing additional cytokines, chemokines, and adhesion molecules (1-5). Elevated plasma IL-18 levels have been detected in patients with acute coronary syndromes (6), and a direct correlation between IL-18 levels and the severity of myocardial dysfunction has been reported. Circulating IL-18 levels have been shown to be independent predictors of coronary events in humans, with increased basal levels of IL-18 observed in individuals who later developed coronary events (7). Increased circulating IL-18 levels have also been measured during heart failure as well as in stroke patients (8, 9). IL-18 signals via the IL-18 receptor, a heterodimer consisting of a ligand binding ␣-subunit and a signal-transducing ␤-subunit (10, 11). Binding of IL-18 to IL-18R␣ recruits IL-18R␤, and this activated complex initiates pleiotropic signal transduction events. Similar to IL-1 receptor antagonist that blocks IL-1 signaling, IL-18-binding protein (IL-18BP) binds IL-18 with high affinity, inhibits IL-18 bioavailability (12), neutralizes IL-18 effects, and thus reduces inflammation. Interestingly, transgenic mice overexpressing human IL-18BP exhibit reduced inflammation and disease severity (13).Cytotoxic free radicals and proinflammatory cytokines are produced during ischemia/reperfusion (I/R) injury. Using isolated adult rat cardiomyocytes, we have recently described NF-B-dependent IL-18 and IL-18R␤ expression following hydrogen peroxide and TNF-␣ treatment in vitro (14). Moreover, although IL-18BP gene expression under basal conditions in these cells is undetectable, TNF-␣ and H 2 O 2 each induce IL-18BP mRNA in a delayed but persistent manner (14), which suggests tight regulation of IL-18 bioavailability. However, the precise role of IL-18 in I/R injury and its regulation in vivo are incompletely understood, and the signal transduction path-* This work was supported in part by the Research Service of the Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Level and Value of Interleukin-18 After Acute Ischemic Stroke

Cited by 47 publications

References 31 publications

Increased Levels of Serum IL-18 Are Associated with the Long-Term Outcome of Severe Traumatic Brain Injury

Increased Levels of Serum IL-18 Are Associated with the Long-Term Outcome of Severe Traumatic Brain Injury

Interleukin-18 induces EMMPRIN expression in primary cardiomyocytes via JNK/Sp1 signaling and MMP-9 in part via EMMPRIN and through AP-1 and NF-κB activation

Neutralization of Interleukin-18 Ameliorates Ischemia/Reperfusion-induced Myocardial Injury

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