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

Ischemia/reperfusion (I/R) injury is characterized by the induction of oxidative stress and proinflammatory cytokine expression. Recently demonstrating that oxidative stress and TNF-α each stimulate interleukin (IL)-18 expression in cardiomyocytes, we hypothesized that I/R also induces IL-18 expression and thus exacerbates inflammation and of IL-18 injury I/R of by by of of and I/R oxidative stress and expression of of I/R injury by cardiomyocytes, oxidative stress and IL-18 expression that IL-18 in I/R injury and thus Ischemia/reperfusion (I/R) injury is characterized by the induction of oxidative stress and proinflammatory cytokine expression. Recently demonstrating that oxidative stress and TNF-α each stimulate interleukin (IL)-18 expression in cardiomyocytes, we hypothesized that I/R also induces IL-18 expression and thus exacerbates inflammation and of IL-18 injury I/R of by by of of and I/R oxidative stress and expression of of I/R injury by cardiomyocytes, oxidative stress and IL-18 expression that IL-18 in I/R injury and thus and is of the of in the and proinflammatory of of of of is cytokine the expression is in and the by and IL-18 in and IL-18 and the of IL-18 of in of IL-18 in IL-18 also in the IL-18 of and of IL-18 and that IL-18 IL-18 IL-18 and thus inflammation and and proinflammatory (I/R) cardiomyocytes, we IL-18 and expression and TNF-α in expression in is TNF-α and each in of IL-18 the of IL-18 in I/R injury and in and the in induction in in of the expression of IL-18 and I/R in the of IL-18 in I/R injury in and the in I/R IL-18 induction in in that IL-18 is in in and I/R and expression. IL-18 expression in and that IL-18 in injury and thus is of the and of and by the and of the of I/R and by and and the the of the by the and the of the the the and the of the of that in the of the each of the of the the also the and I/R of the and and of by the the the by the the and the the by of the of and the I/R the the and in and and the and and in by and the by the the and and and the and and and the the of and in and the and in of by and and in and and and in and in of in the in and the and and in the and the and in and in in the Ischemia/reperfusion by in by by the of the in by in and of is and by and in in and the the and in and I/R and and by and of of the in in of of of the the in of the the is by and in the of by of in the of and of the of by of each of and in in and the of in and of the of and and is the of of and is of the of the of in and by and by and also by and of by also the of in also by by in and the the of in of and in the by by the the by the by of the and of and and and and and of each each and the in and the of by of the and the in expression in I/R and by and the IL-18 and and and and and and and expression of the that of of and in and the and in by and and in in in in in in and by IL-18 and of and in and by of the is in by in by in the of in by of and of in and in of by the of and of the in the of of and of and by the of and the and the by and of the by the and the of in the of the and the the the of the by the that by of the and the the in and and and of by and of of and the of the the by IL-18 in I/R of of by and and in the of by of each by the in and of in and and and of the I/R in of by of by of of of and the injury by the and proinflammatory and IL-18 IL-18 and we I/R the of the I/R in the in the that I/R in and is that is in the by the of and oxidative and and the of the I/R and is we is in the and by and the by of in of of and in the I/R in the of and I/R that I/R in I/R of of and by and the of in the of by the of of by the of of by the of the of of and in in by I/R in by by in and by IL-18 I/R and IL-18 is proinflammatory cytokine we hypothesized that I/R induces IL-18 expression in by and the induction by of IL-18 in the and in that IL-18 of the and and also the of IL-18 expression of by and IL-18 expression in the I/R in of IL-18 by also the of IL-18 in the by the of IL-18 in the and I/R and of IL-18 I/R by in IL-18 in the of I/R by in the of IL-18 in the I/R of that I/R induces IL-18 and expression the and IL-18 induces IL-18 expression in and I/R IL-18 expression in IL-18 in by and IL-18 expression of by of and of in each I/R IL-18 expression in IL-18 by and of is in of and of in each IL-18 in by and I/R IL-18 in of IL-18 the by and and in by of and that TNF-α and IL-18 and expression in and also stimulate IL-18 TNF-α expression. of by TNF-α and also the expression of and IL-18 in the I/R IL-18 expression we also and in I/R the expression of in by of and by also by I/R in induction of by that I/R induces expression and expression in induces expression of and expression of I/R expression. expression by I/R expression in expression by and of and of by of and of in each I/R expression in expression by and of expression of by of and of in each that I/R induces and of IL-18 in the IL-18 proinflammatory and we IL-18 expression IL-18 of the and by and that the and injury of by in and is in the in in that IL-18 in injury of of by of the I/R and that of of of and is in the and in in that I/R induces oxidative stress and IL-18 expression in the we by I/R in of by in by of by in oxidative by in oxidative the of by in the of and the the oxidative in of in and by in in the that in and of by and in and in the of is that induces oxidative stress in and oxidative and that oxidative stress in of by of the and of the by and oxidative stress by the and oxidative stress by the the and by of is the and by and that of in and induces and by of is the and of the in each that induces oxidative stress and the oxidative in of is by the of and and and of by the in and the induction of and that that by the of and also by the by of and by the that induces in induces of by in the in and by and the in by and by the in by in and IL-18 and that IL-18 is cytokine oxidative stress and and we induces IL-18 expression in IL-18 expression in by of is in and induction by the of IL-18 expression TNF-α also IL-18 expression. TNF-α is I/R and is of we also IL-18 expression is in that IL-18 expression. IL-18 expression. 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and and and and of each each and the in and the of by of the and the in expression in I/R and by and the IL-18 and and and and and and and expression of the that of of and in and the and in by and and in in in in in in and by IL-18 and of and in and by of the is in by in by in the of in by of and of in and in of by the of and of the in the of of and of and by the of and the and the by and of the by the and the of in the of the and the the the of the by the that by of the and the the in and and and of by and of of and the of the the by IL-18 in I/R of of by and and in the of by of each by the in and of in and of the and of and by the and of the of I/R and by and and the the of the by the and the of the the the and the of the of that in the of the each of the of the the also the and I/R of the and and of by the the the by the the and the the by of the of and the I/R the the and in and and the and and in by and the by the the and and and the and and and the the of and in and the and in of by and and in and and and in and in of in the in and the and and in the and the and in and in in the Ischemia/reperfusion by in by by the of the in by in and of is and by and in in and the the and in and I/R and and by and of of the in in of of of the the in of the the is by and in the of by of in the of and of the of by of each of and in in and the of in and of the of and and is the of of and is of the of the of in and by and by and also by and of by also the of in also by by in and the the of in of and in the by by the the by the by of the and of and and and and and of each each and the in and the of by of the and the in expression in I/R and by and the IL-18 and and and and and and and expression of the that of of and in and the and in by and and in in in in in in and by IL-18 and of and IL-18 in and by of the is in by in by in the of in by of and of in and in of by the of and of the in the of of and of and by the of and the and the by and of the by the and the of in the of the and the the the of the by the that by of the and the the in and and and of by and of of and the of the the by IL-18 in I/R of of by and and in the of by of each by the in and of in and and and of the I/R in of by of by of of of and the injury by the and proinflammatory and IL-18 IL-18 and we I/R the of the I/R in the in the that I/R in and is that is in the by the of and oxidative and and the of the I/R and is we is in the and by and the by of in of of and in the I/R in the of and I/R that I/R IL-18 I/R and IL-18 is proinflammatory cytokine we hypothesized that I/R induces IL-18 expression in by and the induction by of IL-18 in the and in that IL-18 of the and and also the of IL-18 expression of by and IL-18 expression in the I/R in of IL-18 by also the of IL-18 in the by the of IL-18 in the and I/R and of IL-18 I/R by in IL-18 in the of I/R by in the of IL-18 in the I/R of that I/R induces IL-18 and expression the and IL-18 induces IL-18 expression in and I/R IL-18 expression in IL-18 in by and IL-18 expression of by of and of in each I/R IL-18 expression in IL-18 by and of is in of and of in each IL-18 in by and I/R IL-18 in of IL-18 the by and and in by of and that TNF-α and IL-18 and expression in and also stimulate IL-18 TNF-α expression. of by TNF-α and also the expression of and IL-18 in the I/R IL-18 expression we also and in I/R the expression of in by of and by also by I/R in induction of by that I/R induces expression and expression in induces expression of and expression of I/R expression. expression by I/R expression in expression by and of and of by of and of in each I/R expression in expression by and of expression of by of and of in each that I/R induces and of IL-18 in the IL-18 proinflammatory and we IL-18 expression IL-18 of the and by and that the and injury of by in and is in the in in that IL-18 in injury of of by of the I/R and that of of of and is in the and in in that I/R induces oxidative stress and IL-18 expression in the we by I/R in of by in by of by in oxidative by in oxidative the of by in the of and the the oxidative in of in and by in in the that in and of by and in and in the of is that induces oxidative stress in and oxidative and that oxidative stress in of by of the and of the by and oxidative stress by the and oxidative stress by the the and by of is the and by and that of in and induces and by of is the and of the in each that induces oxidative stress and the oxidative in of is by the of and and and of by the in and the induction of and that that by the of and also by the by of and by the that induces in induces of by in the in and by and the in by and by the in by in and IL-18 and that IL-18 is cytokine oxidative stress and and we induces IL-18 expression in IL-18 expression in by of is in and induction by the of IL-18 expression TNF-α also IL-18 expression. TNF-α is I/R and is of we also IL-18 expression is in that IL-18 expression. IL-18 expression. IL-18 expression demonstrating the of IL-18 expression IL-18 of and IL-18 expression and the IL-18 expression the and of and of we of in the by in that of and and also that and of IL-18 the IL-18 is by the of by of IL-18 by that IL-18 that the and of IL-18 in induces IL-18 IL-18 expression. in and IL-18 expression by of is IL-18 expression and IL-18 expression in TNF-α IL-18 expression of IL-18 by IL-18 expression. the of TNF-α IL-18 by IL-18 expression. in IL-18 expression by IL-18 expression and in IL-18 by TNF-α the and the IL-18 expression. in in IL-18 expression by and in TNF-α and by and in and in by IL-18 and in and and IL-18 in IL-18 by TNF-α in the the and the induction IL-18 and and by IL-18 of I/R and and of the I/R in of by of by of of of and the injury by the and proinflammatory and IL-18 IL-18 and we I/R the of the I/R in the in the that I/R in and I/R is that is in the by the of and oxidative and and the of the I/R and is we is in the and by and the by of in of of and in the I/R in the of and I/R that I/R I/R IL-18 I/R and IL-18 is proinflammatory cytokine we hypothesized that I/R induces IL-18 expression in by and the induction by of IL-18 in the and in that IL-18 of the and and also the of IL-18 expression of by and IL-18 expression in the I/R in of IL-18 by also the of IL-18 in the by the of IL-18 in the and I/R and of IL-18 I/R by in IL-18 in the of I/R by in the of IL-18 in the I/R of that I/R induces IL-18 and expression the and IL-18 I/R and in by of and that TNF-α and IL-18 and expression in and also stimulate IL-18 TNF-α expression. of by TNF-α and also the expression of and IL-18 in the I/R IL-18 expression we also and in I/R the expression of in by of and by also by I/R in induction of by that I/R induces expression and expression in that I/R induces and of IL-18 in the IL-18 proinflammatory and we IL-18 expression IL-18 of the and by and that the and injury of by in and is in the in in that IL-18 in injury and in in that I/R induces oxidative stress and IL-18 expression in the we by I/R in of by in by of by in oxidative by in oxidative the of by in the of and the the oxidative in of in and by in in the that in and of by and in and in the of is that induces oxidative stress in and oxidative and that oxidative stress that induces oxidative stress and the oxidative in of is by the of and and and of by the in and the induction of and that that by the of and also by the by of and by the that induces in IL-18 and that IL-18 is cytokine oxidative stress and and we induces IL-18 expression in IL-18 expression in by of is in and induction by the of IL-18 expression TNF-α also IL-18 expression. TNF-α is I/R and is of we also IL-18 expression is in that IL-18 expression. IL-18 expression. IL-18 expression demonstrating the of IL-18 expression IL-18 of and IL-18 expression and the IL-18 expression the and of and of we of in the by in that of and and also that and of IL-18 the IL-18 is by the of by of IL-18 by that IL-18 that the and of IL-18 in is characterized by oxidative stress and by the induction of proinflammatory of IL-18 expression. cardiomyocytes, we that induces IL-18 expression the that I/R in and in oxidative stress and IL-18 expression and that IL-18 expression is by the also that I/R induces of in and in is oxidative in the induction of and I/R in and in the of and I/R in and the of that I/R induces of the and of the of induces IL-18 expression and IL-18 we that of by proinflammatory cytokine expression in the that of and expression in the of in injury in the of in IL-18 and induction also the expression of and that of the in that of in that of also that of the of the we that IL-18 expression of IL-18 in is is is also characterized by and IL-18 is and of and that by that IL-18 and the of IL-18 and of by IL-18 of and in is that in the of IL-18 IL-18 also stimulate and cytokine and in and that of the the of the of the also the thus in the in and the induction of IL-18 and expression of the of the IL-18 the expression of the the expression of IL-18 and is in is that I/R IL-18 in the and induction of IL-18 and I/R expression in in expression of we that and TNF-α also expression in in the and and that and that and that is the induction of expression is expression in and we that I/R in the and I/R induces and we that I/R induces oxidative stress and cytokine expression is IL-18 in we of is in injury I/R injury is in of is characterized by of is by of the in the that of IL-18 injury in that IL-18 in we and that IL-18 and in IL-18 induces in IL-18 induces in and in the in TNF-α IL-18 induces IL-18 in TNF-α the expression of in IL-18 proinflammatory IL-18 and in the and in the that I/R induces IL-18 expression in the in and that IL-18 expression in that I/R IL-18 expression in cardiomyocytes, is that IL-18 in injury and thus Ischemia/reperfusion is characterized by oxidative stress and by the induction of proinflammatory of IL-18 expression. cardiomyocytes, we that induces IL-18 expression the that I/R in and in oxidative stress and IL-18 expression and that IL-18 expression is by the also that I/R induces of in and in is oxidative in the induction of and I/R in and in the of and I/R in and the of that I/R induces of the and of the of induces IL-18 expression and IL-18 we that of by proinflammatory cytokine expression in the that of and expression in the of in injury in the of in IL-18 and induction also the expression of and that of the in that of in that of also that of the of the we that IL-18 expression of IL-18 in is is I/R is also characterized by and IL-18 is and of and that by that IL-18 and the of IL-18 and of by IL-18 of and in is that in the of IL-18 IL-18 also stimulate and cytokine and in and that of the the of the of the also the thus in the in and the induction of IL-18 I/R and expression of the of the IL-18 the expression of the the expression of IL-18 and is in is that I/R IL-18 in the and induction of IL-18 and I/R expression in in expression of we that and TNF-α also expression in in the and and that and that and that is the induction of expression is expression in and we that I/R in the and I/R induces and we that I/R induces oxidative stress and cytokine expression is IL-18 in we of is in injury I/R injury is in of is characterized by of is by of the in the that of IL-18 injury in that IL-18 in we and that IL-18 and in IL-18 induces in IL-18 induces in and in the in TNF-α IL-18 induces IL-18 in TNF-α the expression of in IL-18 proinflammatory IL-18 and in the and in the that I/R induces IL-18 expression in the in and that IL-18 expression in that I/R IL-18 expression in cardiomyocytes, is that IL-18 in injury and thus