Induction of interleukin-6 synthesis in the myocardium. Potential role in postreperfusion inflammatory injury.
BACKGROUND
Neutrophil-induced injury of myocardial cells requires the expression of intercellular adhesion molecule-1 (ICAM-1) on the myocyte surface and is mediated by ICAM-1-CD11b/CD18 adhesion. We have previously shown that interleukin-6 (IL-6) cytokine activity, present in cardiac lymph, induces ICAM-1 on isolated cardiac myocytes. Furthermore, in previous in vivo studies, we have also shown ICAM-1 mRNA induction in the myocardium within the first hour of reperfusion in the previously ischemic viable zone. We hypothesized that induction of IL-6 synthesis in the myocardium was an integral part of the reaction to injury resulting from ischemia and reperfusion and was associated with induction of ICAM-1 on myocardial cells.


RESULTS
In this study, cloned canine IL-6 cDNA was used as a molecular probe to study the regulation of IL-6 in an awake canine model of myocardial ischemia and reperfusion. IL-6 mRNA was induced in ischemic and reperfused segments of myocardium preferentially in segments previously exposed to severe ischemia. Peak levels of IL-6 mRNA were reached within 3 hours of reperfusion. At the same time, IL-6 mRNA and ICAM-1 mRNA were found in the same myocardial segments. In contrast to hearts that were ischemic for 1 hour and reperfused for 3 hours, nonreperfused hearts after 4 hours of persistent ischemia demonstrated minimal induction of ICAM-1 or IL-6 despite similar degrees of injury and blood flow reductions during ischemia. After 24 hours of persistent ischemia, levels of IL-6 mRNA were comparable to those observed in hearts that were ischemic for 1 hour and subsequently reperfused for 24 hours.


CONCLUSIONS
Our results demonstrate induction of IL-6 mRNA in the myocardium and that this synthesis is accelerated by reperfusion. Evidence is also provided to show that peak IL-6 mRNA precedes that of ICAM-1 mRNA. These findings are compatible with our hypothesis that IL-6 is important in the induction of ICAM-1 in the area of ischemia. In addition, these studies suggest that the necessary factors to promote adhesive interactions between transmigrated neutrophils and cardiac myocytes are present in reperfused myocardium.
Kukielka
G L
GL
Section of Cardiovascular Sciences, Methodist Hospital, DeBakey Heart Center, Houston, Tex, USA.
Smith
C W
CW
Manning
A M
AM
Youker
K A
KA
Michael
L H
LH
Entman
M L
ML
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D018076:DNA, Complementary; D004285:Dogs; D005260:Female; D015870:Gene Expression; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D013552:Swine; D013997:Time Factors
D018076:DNA, Complementary; D015850:Interleukin-6; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1