Pretreatment of normal humans with monophosphoryl lipid A induces tolerance to endotoxin

Astiz, Mark E.; Rackow, Eric C.; Still, James; Howell, Scott; Cato, Allen; Eschen, Kenneth B. Von; Ulrich, J. Terry; Rudbach, Jon A.; McMahon, Gilbert; Vargas, Ramón; Stern, Warren C.

doi:10.1097/00003246-199501000-00006

Cited by 128 publications

(93 citation statements)

References 24 publications

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“…Endotoxin tolerance can be induced both in vitro and in vivo. [8][9][10] Immune cells in vitro, especially monocytes and macrophages, are rendered tolerant when they are exposed to low concentrations of endotoxin and exhibit a suppressed proinflammmatory mediator production when they are subjected to a secondary challenge with endotoxin. This phenomenon, also known as 'cell reprogramming', is also seen after priming with other bacterial components or with proinflammatory cytokines.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator activated receptor γ is not necessary for the development of LPS‐induced tolerance in macrophages

Zingarelli¹,

Ashton²,

Piraino³

et al. 2008

Immunology

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SummaryPeroxisome proliferator activated receptor-c (PPARc) has been reported to exert anti-inflammatory properties in endotoxic shock and sepsis. One phenomenon that alters the inflammatory response to endotoxin [lipopolysaccharide (LPS)] is endotoxin tolerance, which is caused by previous exposure to endotoxin. Here, we investigate whether changes in endogenous PPARc function regulate this phenomenon using three different models of LPS-induced tolerance in macrophages. In a first in vitro model, previous LPS exposure of murine J774.2 macrophages suppressed tumour necrosis factor-a (TNF-a) release in response to subsequent LPS challenge. Treatment of J774.2 cells with the PPARc inhibitor GW9662 did not alter tolerance induction because these cells were still hyporesponsive to the secondary LPS challenge. In a second ex vivo model, primary rat peritoneal macrophages from LPS-primed rats exhibited suppression of thromboxane B 2 and TNF-a production, while maintaining nitrite production in response to in vitro LPS challenge. Pretreatment of rats with the PPARc inhibitor GW9662 in vivo failed to alter the tolerant phenotype of these primary macrophages. In a third ex vivo model, primary peritoneal macrophages with conditional deletion of PPARc were harvested from LPS-primed Cre-lox mice (Cre +/+ PPARc )/) ) and exhibited significant suppression of TNF-a production in response to in vitro LPS challenge. Furthermore, both LPS-primed PPARc-deficient Cre +/+ PPARc )/) mice and wild-type Cre )/) PPARc +/+ mice exhibited reduced plasma TNF-a levels in response to a high dose of LPS in vivo. These data demonstrate that PPARc does not play a role in the LPS-induced tolerant phenotype in macrophages.

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Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator activated receptor γ is not necessary for the development of LPS‐induced tolerance in macrophages

Zingarelli¹,

Ashton²,

Piraino³

et al. 2008

Immunology

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“…The general chemical structure of LPA from diverse gram-negative bacteria is highly conserved (40). LPA has the biological function to induce nuclear factor-B activation in monocytes (24) and the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-␣) and interleukin-1 (IL-1) from macrophages (2,16). The acute-phase reactant LPS binding-protein (LBP) binds to the LPA moiety with high affinity and facilitates the transfer of LPS to CD14 (38,40,44).…”

mentioning

confidence: 99%

N-Linked Glycosylation Is Required for C1 Inhibitor-Mediated Protection from Endotoxin Shock in Mice

Scafidi

et al. 2004

Infect Immun

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C1 inhibitor (C1INH) prevents endotoxin shock in mice via a direct interaction with lipopolysaccharide (LPS). This interaction requires the heavily glycosylated amino-terminal domain of C1INH. C1INH in which N-linked carbohydrate was removed by using N-glycosidase F was markedly less effective in protecting mice from LPS-induced lethal septic shock. N-deglycosylated C1INH also failed to suppress fluorescein isothiocyanate (FITC)-LPS binding to and LPS-induced tumor necrosis factor alpha mRNA expression by the murine macrophage-like cell line, RAW 264.7, and cells in human whole blood. In an enzyme linked immunosorbent assay, the N-deglycosylated C1INH bound to LPS very poorly. In addition, C1INH was shown to bind to diphosphoryl lipid A (dLPA) but only weakly to monophosphoryl lipid A (mLPA). As with intact LPS, binding of N-deglycosylated C1INH to dLPA and mLPA was diminished in comparison with the native protein.Removal of O-linked carbohydrate had no effect on any of these activities. Neither detoxified LPS, dLPA, nor mLPA had any effect on the rate or extent of C1INH complex formation with C1s or on cleavage of the reactive center loop by trypsin. These data demonstrate that N-linked glycosylation of C1INH is essential to mediate its interaction with the LPA moiety of LPS and to protect mice from endotoxin shock.Septic shock caused by gram-negative bacteria is due primarily to endotoxin lipopolysaccharide (LPS), which is a complex glycolipid found in the outer membrane of all gram-negative bacteria (6). Treatment of gram-negative bacterial infections would be greatly aided by substances that can effectively block production of inflammatory mediators from LPS-induced mononuclear phagocytes. Administration of LPS to humans or experimental animals results in many of the physiological changes observed during gram-negative bacterial infection, including fever, hypotension, hypoglycemia, disseminated intravascular coagulation, and shock (5). LPS is composed of two chemically dissimilar structural regions: the hydrophilic repeating polysaccharide of the core and O-antigen structures and a hydrophobic domain known as lipid A (LPA) (40). LPA is the toxic principle of gram-negative bacterial LPS and has full endotoxin activity (15,38). Virtually all LPS-induced biological responses are LPA dependent (33). Therefore, recognition of LPA by cells must be the initial step in LPSinduced cellular responses. The general chemical structure of LPA from diverse gram-negative bacteria is highly conserved (40). LPA has the biological function to induce nuclear factor-B activation in monocytes (24) and the production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-␣) and interleukin-1 (IL-1) from macrophages (2, 16). The acute-phase reactant LPS binding-protein (LBP) binds to the LPA moiety with high affinity and facilitates the transfer of LPS to CD14 (38,40,44). LPA contains the binding domain recognized by LPS-binding proteins, but the polysaccharide O chain and oligosaccharide core structure of endotoxin ...

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“…The NLRP3 inflammasome as a therapeutic target for MPLA It has been well established that MPLA can be administered prior to LPS treatment for the induction of 'endotoxic tolerance', which is characterized by reduced inflammatory cytokine production, decreased febrile response and heart rate [60). MPLA pretreatment of organs to be transplanted also prevents cell death subsequent to tissue reperfusion (7), an event partially mediated by IL-113 production (12).…”

Section: Chapter Vi: Discussionmentioning

confidence: 99%

“…Pretreatment with intravenous MPLA prior to administration of endotoxin protects patients against LPS-induced fever and tachycardia; MPLA-treated patients also displayed reduced serum levels of TNF, IL-6 and IL-8 versus patients pretreated with vehicle control [60]. The inhibition of LPS-induced proinflammatory cytokines by MPLA has been confirmed using animal models of septic shock [61, …”

Section: Il-1 Receptorsmentioning

confidence: 99%

“…This is intriguing considering that MLA can be used to prevent ischemic reperfusion injury [74][75][76][77][78][79], whose pathology is mediated in part by IL-1J3 [70]. MLA's effectiveness at inducing a tolerant state whereby cells are temporarily unresponsive to further stimulation through TLR4 has been demonstrated in both humans and several animal models [60][61][62]104]. Tolerance of this kind is achievable using endotoxin itself (LPS or Lipid A), however these TLR4 agonists induce a toxic inflammatory response prior to acquisition of tolerance [105,106].…”

Section: Mla Weakly Induces Nlrp3 Transcript and Protein In Myeloid Dcsmentioning

confidence: 99%

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Reconciliation of IL-1ß loss with TRIF-biased TLR4 signaling by monophosphate lipid A.

Embry¹

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Monophosphoryl Lipid A (MPLA), a derivative of LPS endotoxin, is a TLR4 agonist that displays as little as 0.1-1% as much toxicity as its parent molecule while retaining immunostimulatory properties. We discovered that MPLA activates a TRIF-biased pattern of TLR4 signaling, resulting in reduced production of MyD88-dependent pro-inflammatory factors, and credited TRIF-bias for MPLA's reduced toxicity. A contemporary study showed that MPLA fails to promote maturation of the potent inflammatory cytokine IL-1 J3. This dissertation seeks to reconcile MPLA's TRIF-biased signaling with IL-1J3 loss, and to determine the ultimate cause of MPLA's reduced toxicity compared to LPS. We find that TRIF-biased TLR4 activation results in weak MyD88-dependent induction of NLRP3, a critical inflammasome component required for IL-1 J3 production. MPLA's loss of IL-1J3 results in decreased potentiation of MyD88-dependent inflammatory factors in vivo and reduced IL-1 RI-dependent hepatotoxicity. Ultimately, TRIFbiased TLR4 signaling is the causative factor resulting in MPLA's immunogenicity with low toxicity; however more studies are needed to determine the initial events leading to the TRIFdependent Signaling cascade. This dissertation describes the mechanisms responsible for MPLA's reduced induction of inflammatory responses and outlines how this signaling may be exploited for therapeutic use.

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Pretreatment of normal humans with monophosphoryl lipid A induces tolerance to endotoxin

Cited by 128 publications

References 24 publications

Peroxisome proliferator activated receptor γ is not necessary for the development of LPS‐induced tolerance in macrophages

Peroxisome proliferator activated receptor γ is not necessary for the development of LPS‐induced tolerance in macrophages

N-Linked Glycosylation Is Required for C1 Inhibitor-Mediated Protection from Endotoxin Shock in Mice

Reconciliation of IL-1ß loss with TRIF-biased TLR4 signaling by monophosphate lipid A.

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