Regulation of CCAAT/Enhancer binding protein, interleukin-6, interleukin-6 receptor, and gp130 expression during myocardial ischemia/reperfusion

Abstract

Background: Interleukin (IL)-6 is elevated in myocardium after ischemia and reperfusion. The IL-6 promoter/enhancer region contains response elements for nuclear factor-kappaB, AP-1, and CCAAT/enhancer binding protein (C/EBP). Expression and regulation of C/EBP in rat myocardium after ischemia and reperfusion has not been defined, nor has the behavior of the specific IL-6 receptor (IL-6R) or the signal transducer gp130.

Methods and results: C/EBP DNA binding activity was not detected in shams or in previously ischemic tissue at 15 minutes of reperfusion; it was detected at 30 minutes of reperfusion, increased at 1 hour of reperfusion, and declined by 6 hours of reperfusion. A supershift was observed with anti-C/EBP-beta but not with anti-alpha or anti-delta antibodies. mRNA and protein levels of IL-6 and gp130 were detected at low levels in controls, increased at 1 hour of reperfusion, and remained high until 6 hours of reperfusion. IL-6R mRNA and protein were not detected in controls, but its mRNA was induced at 1 hour of reperfusion and its protein at 2 hours of reperfusion. Although effects of reperfusion were rapid, in ischemic tissue not reperfused, low levels of C/EBP were detected at 4 hours, and at 24 hours the levels were slightly elevated. Significant upregulation in IL-6, IL-6R, and gp130 occurred only at 24 hours of sustained ischemia.

Conclusions: Reperfusion after a brief period of ischemia caused induction of myocardial C/EBP (beta-subunit). The rapid and sustained production of IL-6 with concomitant expression of IL-6 receptor and gp130 suggest that these factors may participate in a local inflammatory cascade after myocardial ischemia and reperfusion.