Dissociation between plasma and monocyte‐associated cytokines during sepsis

Abstract

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.

Enhanced Interleukin-6 and Interleukin-8 Synthesis in Term and Preterm Infants

“…This is mandatory because functional responses of purified cell preparations may not represent physiologic reactions occurring in vivo (27). Furthermore, a dissociation between plasma and cell-associated cytokines during sepsis (28) warrants cytokine analysis at the single cell level.…”

Monitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony

“…These tests represent reliable methods to assess the phenomenon of endotoxin tolerance defined as a reduced responsiveness to a secondary LPS challenge following a first inflammatory response. Monocytes from septic patients usually present with a diminished capacity to release tumor necrosis factor (TNF)-α, IL-1α, IL-6, and IL-12, whereas the release of anti-inflammatory mediators (IL-1ra, IL-10) is not affected or even slightly increased (33)(34)(35)(36)(37)(38). This shows that LPS can still activate monocytes but that the intracellular signaling has been turned to favor production of anti-inflammatory molecules, therefore supporting the concept of leukocyte reprogramming (39,40).…”

Mitogen-Activated Protein Kinase Phosphatase 1 Disrupts Proinflammatory Protein Synthesis in Endotoxin-Adapted Monocytes

“…This twophase sepsis response occurs in animals (16) and humans (7), and its repressive component is mirrored by the presence of refractory TLR responses. The sustained repression of proinflammatory genes in blood monocytes (17) and neutrophils (18) during the late phase of acute systemic inflammation is mirrored by endotoxin adaptation or " tolerance," a process that can be modeled in cultures of primary monocytes and human monocytic cell lines such as THP-1 cells stimulated by bacterial endotoxin (lipopolysaccharide [LPS]) (13,(19)(20)(21). Endotoxin-adapted THP-1 cells, monocytes/macrophages, and neutrophils from septic patients fail to produce proinflammatory TNF-␣, IL-6, and IL-1␤ in response to subsequent stimulation with LPS (13,18,(22)(23)(24).…”