In vivo endotoxin tolerance

Endotoxin tolerance is defined as a reduced responsiveness to a lipopolysaccharide (LPS) challenge following a first encounter with endotoxin. Endotoxin tolerance protects against a lethal challenge of LPS and prevents infection and ischemia-reperfusion damage. Endotoxin tolerance is paralleled by a dramatic reduction of tumor necrosis factor (TNF) production and some other cytokines in response to LPS. Endotoxin tolerance involves the participation of macrophages and mediators, such as glucocorticoids, prostaglandins, IL-10, and transforming growth factor-β. Endotoxin tolerance is accompanied by the up-regulation of inhibitory molecules that down-regulate the Toll-like receptor (TLR)4dependent signaling pathway. Cross-tolerance between LPS and other TLR specific ligands, as well as IL-1 and TNF, has been regularly reported. A similar loss of LPS reactivity has been repeatedly reported in circulating leukocytes of septic patients and in patients with non-infectious systemic inflammation response syndrome (SIRS). Studies on cellular signaling within leukocytes from septic and SIRS patients reveal numerous alterations reminiscent of those observed in endotoxin tolerant cells. However, altered responsiveness to LPS of leukocytes from sepsis and SIRS patients is not synonymous with a global down-regulation of cellular reactivity. The term ‘cellular reprogramming’, which has been proposed to qualify the process of endotoxin tolerance, defines well the immune status of circulating leukocytes in septic and SIRS patients. In vivo endotoxin tolerance Paul Beeson first reported endotoxin tolerance in 1946 [1] as the abolition of the fever response of rabbits undergoing repeated daily injection of the same dose of typhoid vaccine. Later, it was shown that plasma of a tolerant rabbit could passively transfer tolerance to pyrogenicity of bacterial endotoxin to another animal [2]. In human volunteers, it was shown that inoculation of live Salmonella typhosa led to a reduced fever in response to endotoxin or killed bacteria compared to before infection [3]. Interestingly, a similar observation was reported with volunteers inoculated with Plasmodium cynomolgi by mosquito bites [4], suggesting that cross-tolerization between different stimuli could occur. In addition to human volunteers, reduced fever to endotoxin or killed bacteria was reported in different infections, such as in patients with pyelonephritis [5], in patients convalescent from typhoid and paratyphoid fever [6], and in patients recovering from malaria [7]. Not only can a pretreatment with endotoxin reduce subsequent lipopolysaccharide (LPS)-induced fever in rabbits, it also prevents LPS-induced lethality [8]. In mice, even when LPS-induced lethality was dramatically enhanced by galactosamine treatment, LPS tolerization could prevent mortality [9]. By specific cell transfer from LPS-resistant to LPS-sensitive mice, Freudenberg and Galanos [9] elegantly demonstrated the role of macrophages in the induction of endotoxin tolerance in vivo. Endotoxin tolerance and cytokine production Tumor necrosis factor (TNF) is most probably the best marker of endotoxin tolerance as assessed by its dramatically reduced production following an LPS challenge in tolerized animals, in contrast to its sharp and fast peak in response to a first injection of LPS [10]. Interestingly, not all cytokines behave similarly. In mouse models of endotoxin tolerance, IL-6 and IFN-γ released in the circulation following an LPS challenge are also dramatically blunted, whereas this is not the case for IL-12p70, and the chemokines KC and MCP-1, the circulating levels of which were reduced but not as much as TNF and the previously mentioned cytokines [11]. In contrast, levels of IL-1β and IL-18 were maintained independently of the tolerization process. In humans, induction of tolerance by monophosphoryl lipid A led to a reduction of circulating TNF, IL-6 and IL-8 in response to a subsequent LPS challenge [12]. Review Bench-to-bedside review: Endotoxin tolerance as a model of leukocyte reprogramming in sepsis Jean-Marc Cavaillon and Minou Adib-Conquy Cytokines and Inflammation Unit, Institut Pasteur, rue Dr Roux, 75015 Paris, France Corresponding author: Jean-Marc Cavaillon, [email protected] Published: 13 October 2006 Critical Care 2006, 10:233 (doi:10.1186/cc5055) This article is online at http://ccforum.com/content/10/5/233 © 2006 BioMed Central Ltd IFN = interferon; IL = interleukin; IRAK = IL-1 receptor associated kinase; LPS = lipopolysaccharide; MyD = myeloid differentiation; NF-κB = nuclear factor-kappa B; PBMC = peripheral blood mononuclear cell; RCA = resuscitated after cardiac arrest; SIGIRR = single immunoglobulin IL-1R-related molecule; SIRS = systemic inflammation response syndrome; SOCS = suppressor of cytokine signaling; TGF = transforming growth factor; TLR = Toll-like receptor; TNF = tumor necrosis factor; Tollip = Toll interacting protein; TRAF = TNF receptor associated factor.