Mechanism of endotoxin desensitization: involvement of interleukin 10 and transforming growth factor beta.

Abstract

SummaryTolerance of monocytes/macrophages to endotoxin (lipopolysaccharide [LPS]) can be induced both in vivo and in vitro by LPS itself. Exposure to LPS, even at a very low dose, induces a downregulation of cytokine response to a second high dose LPS challenge. To learn more about the unknown mechanisms of this phenomenon, we studied the role of antiinflammatory cytokines in this process. Preculture of human peripheral blood monocytes for 24 hours with low concentrations of LPS induced hyporesponsiveness to high-dose LPS rechaUenge with respect to tumor necrosis factor (TNF) c~ and interleukin (IL) 10 but not IL-1RA production. These results suggest that LPS tolerance reflects a functional switch of monocytes rather than a general LPS hyporesponsiveness. IblO and transforming growth factor (TGF) 31 showed additive effects in replacing LPS for induction of LPS hyporesponsiveness in vitro. Additionally, neutralizing anti-IL-10 and anti-TGF-~ monoclonal antibodies prevented induction of LPS tolerance. In vitro induced LPS tolerance looks like the ex vivo LPS hyporesponsiveness of monocytes from septic patients with fatal outcome: downregulation of LPS-induced TNF-oe and IL-10 production but not of IL-1RA secretion. LPS hyporesponsiveness in septic patients was preceded by expression of 11.-10 at both the mRNA and protein level. In summary, our data suggests that IL-10 and TGF-~ mediate the phenomenon of LPS tolerance in vitro and perhaps in vivo (septic patients), too.M onocytes and macrophages are highly sensitive for LPS, reacting on encounter with even traces by synthesis of inflammatory mediators. Among them, a network of proinflammatory cytokines is of special importance for the coordinated activation of the immune system in response to microbial invasion. When local infection develops into sepsis, a strong systemic reaction occurs, and cytokines normally restricted to areas of local injury can be detected systemically causing symptoms of septic shock (1). Although whole-body inflammation is frequently initiated by LPS, a single sublethal injection of LPS also renders the host temporarily refractory to subsequent LPS challenge as well as to other inflammatory stimuli. This phenomenon, referred to as endotoxin tolerance may be at least partially due to a reduced capacity of monocytes/macrophages to synthesize cytokines upon reexposure to LPS (2). The phenomenon of in vivo LPS desensitization has been reproduced in vitro using murine or human monocytes/macrophages (3-5). The mechanisms of LPS tolerance are not clear so far. Modulation of LPS-binding sites (CD14), secretion of inhibitory mediators by desensitized monocytes, and an altered intracellular signaling have been discussed (3,(6)(7)(8).Antiinflammatory mediators such as I1.-10, TGF-B, or IL-1RA which are produced also by monocytes after LPS contact but with delayed kinetics, are thought to be important for downregulating the inflammatory cascade, and they are known to be protective in animal models of sepsis. We wondered whether (a) the production of an...

Interleukin-1β inducesin vivotolerance to lipopolysaccharide in mice

“…The phenomenon of LPS desensitization to its own action, frequently referred to as tolerance to LPS [1,11,24,25], can be induced following natural infection of patients with Gramnegative bacteria, or experimentally by the administration of low doses of LPS [3,12,26]. Endotoxin tolerance is neither a mechanism of cell anergy induction nor a passive process that occurs in an exhausted cell (macrophage).…”

“…Substantial evidence from in vitro and in vivo studies suggests that the response to LPS involves not only rapid secretion of these pro-inflammatory cytokines but also, the concomitant induction of potent anti-inflammatory products [7][8][9]. The latter can be induced by minute amounts of LPS, which render the host temporarily refractory to subsequent lethal doses of LPS challenge, as well as to other inflammatory stimuli [6].…”

“…The latter can be induced by minute amounts of LPS, which render the host temporarily refractory to subsequent lethal doses of LPS challenge, as well as to other inflammatory stimuli [6]. This phenomenon, known as LPS or endotoxin tolerance, shows a reduced capacity of monocytes/macrophages to synthesize pro-inflammatory cytokines upon re-exposure to LPS [3,[9][10][11][12].…”

“…Endotoxin desensitization has also been achieved in vitro with relative efficacy by individual cytokines, such as IL-10 [9] and transforming growth factor-b (TGF-b) [9], and in vivo by injection of IL-13 [8] and IL-1a [13].…”

Immunoparalysis and Adverse Outcomes from Critical Illness

“…The concept of "endotoxin tolerance" represents an experimental analogue to the clinical entity of immunoparalysis. Culturing monocytes or monocytic cells lines in the presence of IL-10 or TGFβ, for example, will induce a state of hyporesponsiveness to subsequent LPS challenge [34][35][36]. Perhaps the best inducer of experimental endotoxin tolerance is endotoxin itself.…”