Tumor necrosis factor, interleukin 6, and the acute phase response following hepatic ischemia/reperfusion

We report here the production of systemic levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) and associated changes in serum macroglobulin to albumin ratios in a nonlethal rat model of partial hepatic ischemia/reperfusion (I/R). Plasma IL-6 was detectable and elevated at 1 hr of reperfusion as compared to sham-operated controls (I/R rats = 12,100 +/- 3860 pg/ml; sham rats = 5260 +/- 842 pg/ml; IL-6 values = means +/- SEM) and reached maximal levels at 6 hr of reperfusion (I/R rats = 47,400 +/- 25,700 pg/ml; sham rats = 3370 +/- 394 pg/ml), in contrast to maximal TNF levels at 30 min of reperfusion (I/R rats = 72 +/- 15 pg/ml; sham rats = 2 +/- 2 pg/ml; TNF values = means +/- SEM). Pretreatment with neutralizing TNF antisera prior to ischemia resulted in a reduction of IL-6 at 1 hr of reperfusion (anti-TNF = 3870 +/- 2550 pg/ml; control serum = 7650 +/- 1670 pg/ml), but was without effect on IL-6 levels at subsequent time points over the 24 hr of reperfusion. Electrophoretic determination of macroglobulin (alpha 1 + alpha 2) and albumin concentrations in sham-operated and ischemia/reperfusion animals demonstrated an elevation in the macroglobulin/albumin ratio in both groups over time, suggestive of an acute phase response, and the ratio was unchanged by immunoneutralization of TNF prior to ischemia/reperfusion. We conclude that this model of hepatic ischemia/reperfusion results in temporally distinct systemic elevations in IL-6 and TNF; however, the induction of IL-6 and the associated changes in serum macroglobulin concentration are independent of TNF.