Persistently elevated soluble tumor necrosis factor receptor and interleukin-1 receptor antagonist levels in critically ill patients

Abstract

The appearance of endogenously produced inhibitors against tumor necrosis factor (TNF) (soluble TNF-receptor type I, sTNFR-I) and interleukin-1 (IL-1 receptor antagonist, IL-1ra) was evaluated acutely in five normal patients after experimental endotoxemia lipopolysaccharide (LPS) and prospectively during a one to 11 week period in 12 septic, critically ill patients. Increased levels of both factors remained detectable in the circulation for up to 24 hours after LPS (2 nanograms per kilogram body weight) administration in normal patients. Despite free TNF-a activity being detected only sporadically (3 percent of the samples) and that IL-1 beta was never detectable in the patients in the intensive care unit, IL-6 bioactivity was present in 90 percent of initial samples. Circulating sTNFR-I levels up to 62,000 picograms per milliliter and IL-1ra levels of 14,800 picograms per milliliter were noted in the critically ill patients and remained consistently detectable throughout the extended period of evaluation. While there was no difference in IL-1ra levels between patients who survived or ultimately died, sTNFR-I levels were significantly (p < 0.001) lower in survivors compared with nonsurvivors. A correlation between circulating sTNFR-I and concurrent cortisol levels (r = 0.64; p < 0.002) was also noted. Furthermore, a correlation between sTNFR-I and the severity of initial insult, as assessed by APACHE II scores (r = 0.54; p < 0.01) was demonstrable. These naturally occurring cytokine antagonists likely represent additional indicators of the presence of an infectious or other inflammatory process and seem to persist in the circulation even during conditions in which their respective proinflammatory cytokines are not demonstrable.