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.