HYPOXIC STRESS INDUCES CARDIAC MYOCYTE-DERIVED INTERLEUKIN-6

Background Hypoxic and ischemic stresses cause a series of well-docume nted changes in myocardial cells and tissues, including loss of contra ctility, changes in lipid and fatty acid metabolism, and irreversible membrane damage leading to eventual cellular death. Activated neutroph ils are considered to be involved in this myocardial cellular injury. By stimulation of the neutrophils with chemotactic factors, canine neu trophils can be induced to adhere to isolated cardiac myocytes only if the myocytes have been previously exposed to cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, and IL-6. Methods and Resul ts To examine the possible involvement of IL-6 in ischemia-reperfusion injury, we used cultured rat neonatal cardiac myocytes to study the e ffects of hypoxic stress on the production of IL-6 by cardiac myocytes . Unstimulated cardiac myocytes (3x10(5) cells per dish) produced 320 pg IL-6 over 4 hours in vitro tie, biological activity equal to 320 pg recombinant IL-6, as detected by bioassay using the MH-60.BSF2 cell l ine). The incubation of cardiac myocytes under hypoxic conditions for 4 hours induced significantly increased production of IL-6 compared wi th normoxic conditions (2.82+/-0.49 versus 1.64+/-0.18 U/mL, P<.05). F urthermore, reoxygenation for 2 hours after 2 hours of hypoxic stress significantly augmented the production of IL-6 by cardiac myocytes (4. 34+/-0.52 U/mL, P<.05). These responses to hypoxia and reoxygenation w ere not observed in fibroblasts isolated from the same tissue. Althoug h unstimulated cardiac myocytes lacked IL-6 mRNA expression detectable by Northern blot analysis, hypoxic stress induced the expression of I L-6 mRNA in the cardiac myocytes. Several pathophysiologically relevan t factors also augmented IL-6 release from cultured cardiac myocytes, including IL-1 beta, ionomycin, and epinephrine. Conclusions Cardiac m yocytes respond to hypoxic stress to augment the production of IL-6, a nd the IL-6 derived from cardiac myocytes may play an important role i n the progression of myocardial dysfunction observed in cardiac ischem ia-reperfusion injury.