INTERLEUKIN-1, INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA RELEASE IS DOWN-REGULATED IN WHOLE-BLOOD FROM SEPTIC PATIENTS

Proinflammatory cytokines are important mediators during endotoxemia. In experimental models, injection of lipopolysaccharide (LPS) activate s macrophages leading to excessive secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6; infusion of high doses of these mediators results in organ failure and death. Natural infecti on may be different, because it persists over days or even weeks, with repeated endotoxin challenge to macrophages. Little is known about th e capacity of peripheral blood mononuclear cells (PBMCs) to release pr oinflammatory cytokines under these conditions. Therefore, as an ex vi vo model of sepsis, the expression of proinflammatory cytokines after stimulation of whole blood with LPS was studied. A high LPS dose (1 mu g/ml) maximally increased TNF-alpha, IL-1 beta and IL-6 secretion in controls, but a marked depression was observed in septic patients (p < 0.01; 15 patients with severe sepsis versus 20 control patients witho ut infection). This reduction persisted for up to 10 days after diagno sis of sepsis. The release of TNF-alpha, IL-1 beta and IL-6 was marked ly decreased in the septic group even when a lower and physiologically more relevant LPS concentration (1 ng/ml) was used. IL-1 beta mRNA wa s similar to controls, but a down-regulation was observed in TNF-alpha and IL-6 transcript levels in PBMCs from the blood of septic patients . This was at least in part due to a marked reduction in TNF and IL-6 mRNA half-life. These results indicate that different mechanisms down- regulate proinflammatory cytokine release in the whole blood of septic patients. Although excessive secretion is known to be deleterious, lo w concentrations of these cytokines are involved in regulating essenti al cellular and humoral immune functions. Thus, the reduced capacity t o express and release adequate amounts of proinflammatory cytokines af ter exposure to endotoxin, as observed in whole-blood PBMCs from septi c patients, may contribute to the development of immunodeficiency.