Reduced muscle protein breakdown in septic rats following treatment with interleukin-1 receptor antagonist

1. The role of interleukin-1 (IL-1) in sepsis-induced muscle proteolysis was assessed by treating septic rats with recombinant IL-1 receptor antagonist (rIL-1ra). 2. In initial experiments, we tested the effectiveness of IL-1ra in preventing muscle proteolysis induced by administration of IL-1. 3. When normal rats were treated with rIL-1 alpha (three intraperitoneal doses of 100 micrograms/kg body weight each over 16 hr), total and myofibrillar muscle protein breakdown rates, measured as release of tyrosine and 3-methylhistidine, respectively, by incubated extensor digitorum longus muscles, were significantly increased. 4. This metabolic response to IL-1 alpha was completely abolished by rIL-1ra, administered as three intraperitoneal doses of 3 mg/kg body weight each over 16 hr. 5. In subsequent experiments, sepsis was induced in rats by cecal ligation and puncture (CLP); non-septic rats were sham-operated. 6. Treatment of septic rats over 16 hr with a total dose of 25 mg/kg body weight of rIL-1ra reduced, but did not normalize, the increased muscle protein breakdown rates seen during sepsis. 7. When the dose of rIL-1ra was more than doubled and given as a constant infusion at a rate of 4.2 mg/kg body weight/hr for 16 hr, the increased rate of muscle proteolysis in septic rats was normalized. 8. The present study offers the first direct evidence that IL-1 is involved in the regulation of muscle proteolysis during sepsis.