Dissociation between plasma and monocyte-associated cytokines during sepsis

We report our investigations of circulating interleukin (IL) 1 beta, IL 6 and tumor necrosis factor (TNF)-alpha, as well as cell-associated IL 1 alpha, IL 1 beta and TNF-alpha in plasma and monocytes of 21 patients with sepsis syndrome and 6 patients with non-septic shock. Longitudinal studies reveal that (a) the most frequent detectable plasma cytokines were TNF-alpha and IL 6, (b) the presence and the kinetics of circulating cytokines were independent of one other, (c) detectable levels of cytokines could be found for a long period of time, and (d) significantly higher levels of IL 6 were found for non-surviving patients. Because of the in vivo half-life of cytokines and of the existence of numerous specific high-affinity receptors, it is quite probable that detectable plasma cytokines represent the excess of produced mediators which have not been trapped by the target cells. TNF-alpha (410 +/- 65 pg/10(6) monocytes) and IL 1 beta (153 +/- 60 pg/10(6) monocytes) were frequently found associated to monocyte lysates (88% and 50%, respectively). Despite the fact that IL 1 alpha is the most abundant cytokine found associated to monocytes following in vitro activation, IL 1 alpha was rarely found in monocytes of intensive care unit patients (29%). No correlation was found to exist between the levels of plasma cytokines and cell-associated cytokines. Some patients had plasma TNF-alpha or IL 1 beta in the absence of the corresponding monocyte-associated cytokine. This observation suggests that cells other than monocytes can participate in the production of circulating cytokines. At the end of the longitudinal study (day 14 +/- 2), only 2/12 surviving patients still had plasma TNF-alpha, whereas 8/12 had monocyte-associated TNF-alpha. These results indicate that activation of monocytes still occurs in patients for whom no plasma cytokines can be detected. Thus, in addition to the measurement of plasma cytokine, measurement of cell-associated cytokine appears useful to assess cytokine production and monocyte activation in vivo.