Peptidoglycan Primes for LPS-Induced Release of Proinflammatory Cytokines in Whole Human Blood

Wang, Jacob E.; Jørgensen, Per; Ellingsen, Espen B.; Almlöf, M.; Thiemermann, Christoph; Foster, Simon J.; Aasen, Ansgar O.; Solberg, Rigmor

doi:10.1097/00024382-200116030-00002

Cited by 61 publications

(52 citation statements)

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“…Yang et al (4) reported the synergistic effect of MDP with LPS or lipoteichoic acid to induce inflammatory cytokine IL-8 in human monocytic cells in culture. Wang et al (7) reported that co-administration of PGN or MDP with LPS caused significantly increased concentrations of TNF-␣ and IL-6 in cultures of whole human blood, whereas the release of IL-10 was not influenced. In contrast, we observed that TNF-␣ concentra- FIG.…”

Section: Discussionmentioning

confidence: 99%

“…A possible explanation for this discrepancy is that we used insoluble PGN to eliminate potential effects of smaller PGN fragments on the responses being measured. Because Wang et al (7) used a sonicated preparation of PGN, their PGN preparation may have included some smaller fragments that might act like MDP. Another difference between the two studies is the type of cell used; this may account for the differences noted.…”

Section: Table III Effect Of Anti-tlr Mabs On the Induction Of Tnf-␣ mentioning

confidence: 99%

“…However, the underlying mechanism of action for MDP has not been fully elucidated. For example, there are discrepancies regarding the involvement of specific receptors, with some investigators indicating that MDP exerts its synergistic effect in human leukocytes in a CD14-dependent manner (7). Others indicate that the response is CD14-and Toll-like receptor 4 (TLR4)-independent in human monocytic cell lines and that MDP up-regulates expression of one of the primary components (MyD88 mRNA) in the TLR-mediated response to LPS (4).…”

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The Origin of the Synergistic Effect of Muramyl Dipeptide with Endotoxin and Peptidoglycan

Wolfert

Murray

Boons

et al. 2002

Journal of Biological Chemistry

136

108

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Although the basis for the high mortality rate for patients with mixed bacterial infections is likely to be multifactorial, there is evidence for a synergistic effect of muramyldipeptide (MDP) with lipopolysaccharide (LPS) on the synthesis of proinflammatory cytokines by mononuclear phagocytes. In this study, co-incubation of human Mono Mac 6 cells with MDP and either LPS or peptidoglycan (PGN) resulted in an apparent synergistic effect on tumor necrosis factor-␣ (TNF-␣) secretion. Although incubation of cells with MDP alone produced minimal TNF-␣, it caused significant expression of TNF-␣ mRNA. These findings suggest that the majority of TNF-␣ mRNA induced by MDP alone is not translated into protein. Furthermore, simultaneous incubation of cells with MDP and either LPS or PGN resulted in TNF-␣ mRNA expression that approximated the sum of the amounts expressed in response to MDP, LPS, and PGN individually. These findings indicate that the apparent synergistic effect of MDP on TNF-␣ production induced by either LPS or PGN is due to removal of a block in translation of the mRNA expressed in response to MDP. In subsequent studies, the effects of MDP alone and its effect on the production of TNF-␣ by LPS and PGN were determined to be independent of CD14, Toll-like receptor 2, and Toll-like receptor 4. These findings indicate that MDP acts through receptor(s) other than those primarily responsible for transducing the effects of LPS and PGN. Successful treatment of patients having mixed bacterial infections is likely to require interventions that address the mechanisms involved in responses induced by a variety of bacterial cell wall components.Bacteremia is a critical problem in intensive care units, accounting for high morbidity and mortality rates. The mortality rate associated with bacteremia exceeds 30% (1, 2). In a recent 12-year clinical study, Gram-positive and Gram-negative bacteria accounted for 46.9 and 31.5% of bacteremic episodes in an intensive care unit, respectively, with Gram-positive organisms being cultured from more patients (3). Further, the incidence of combined infections increased more than 4-fold over the 12-year period and was associated with a mortality rate exceeding 55%. Based on the fact that the majority of the deleterious effects of bacteremia are caused by inflammatory responses to specific bacterial components, these findings suggest that the patient's response to a mixture of Gram-positive and Gram-negative organisms may be heightened to the detriment of the patient.The two most commonly studied components of Gram-positive and Gram-negative bacterial cell walls are peptidoglycan (PGN) 1 and lipopolysaccharide (LPS), respectively. Although Gram-negative bacterial cell walls also contain PGN, its concentration is far greater in the walls of Gram-positive bacteria (4). Proinflammatory effects of these bacterial cell wall components occur both in vitro after treatment of mononuclear phagocytes and in in vivo after exposure of whole animals, with cells and animals being more sensitive to ...

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Section: Discussionmentioning

confidence: 99%

Section: Table III Effect Of Anti-tlr Mabs On the Induction Of Tnf-␣ mentioning

confidence: 99%

mentioning

confidence: 99%

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The Origin of the Synergistic Effect of Muramyl Dipeptide with Endotoxin and Peptidoglycan

Wolfert

Murray

Boons

et al. 2002

Journal of Biological Chemistry

136

108

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“…In this case, we may hypothesize no effect of MDP on expression of CD14 on macrophages. Wang et al (2001), however, reported a 2-fold increase in surface expression of CD14 on monocytes to MDP, and suggested that MDP primes leukocytes for LPSinduced release of proinflammatory cytokines. Due to these contradictory results, it is difficult to say whether the expression of CD14 on macrophages is regulated during initiation and resolution of the inflammatory response caused by the CD14-independent bacterial signal in the same manner as LPS.…”

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confidence: 98%

Expression of macrophage CD14 receptor in the course of experimental inflammatory responses induced by lipopolysaccharide and muramyl dipeptide

Sládek¹,

Rysanek²

2008

Vet. Med. - Czech

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AbstrACt:The aim of this study was to determine whether expression of CD14 on macrophages is regulated differently during initiation and resolution of the inflammatory response caused by CD14-dependent (lipopolysaccharide) and CD14-independent (muramyldipeptide) bacterial signals. In cell suspensions from the site of inflammation we observed two types of macrophages: non-vacuolized ( N MAC) and vacuolized ( V MAC) cells. N MAC (monocyte-like cells) were dominant during the early stage of the inflammatory response, whilst V MAC contained phagocytosed apoptotic neutrophils in various stages of digestion. These latter cells were dominant during resolution (particularly at the last time point of 168 h). Intramammary instillation of muramyldipeptide (MDP) and lipopolysaccharide (LPS) resulted in a significant increase in the total count of CD14+ N MAC after 24 h (muramyldipeptide P < 0.01 and lipopolysaccharide P < 0.05) compared to phosphate buffered saline (PBS). During resolution of the inflammatory response, a gradual decrease in the total count of CD14+ N MAC was observed. The difference compared with PBS was significant at 48 h and 72 h after instillation of both bacterial agents (muramyldipeptide: P < 0.05; lipopolysaccharide: P < 0.05). A lower total count of CD14+ V MAC was observed as an effect of MDP and LPS at 24 h after induction (P < 0.05), when compared to PBS. During resolution, the total count of CD14+ V MAC increased. Differences (P < 0.01) were observed at 72 h and 168 h after LPS compared to PBS. We therefore assume that the expression of CD14 on macrophages is not regulated differently during the inflammatory responses caused by CD14-dependent and CD14-independent bacterial signals. On the other hand, the stage of the inflammatory response to MDP and LPS played an important role in the regulation of CD14 expression on macrophages.

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“…Monocytes from septic patients also show reduced capacity to release TNF-α, IL-1β, IL-6, IL-10, and IL-12 4,5,6 . Among the known TLRs, TLR2 is primarily implicated in recognition of Gram positive cell wall components, especially peptidoglycan (PGN) which activates immune system cells through TLR2 induced activation of NF-kB, that in turn regulates the expression of various genes involved in cytokine production 7 . TLR2 has received an extra attention due to contrasting reports about its ligand specificity and thereby downstream cytokine tailoring and the consequent immune response 8,9 .…”

Section: Introductionmentioning

confidence: 99%

Expression Analysis of Toll-Like Receptor2 in Bubaline Peripheral Blood Mononuclear Cells upon Stimulation by Bacillus Subtilis Cell Wall Peptidoglycan

Shah¹,

Kumar²

2014

IOSRJAVS

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Peptidoglycan Primes for LPS-Induced Release of Proinflammatory Cytokines in Whole Human Blood

Cited by 61 publications

References 0 publications

The Origin of the Synergistic Effect of Muramyl Dipeptide with Endotoxin and Peptidoglycan

The Origin of the Synergistic Effect of Muramyl Dipeptide with Endotoxin and Peptidoglycan

Expression of macrophage CD14 receptor in the course of experimental inflammatory responses induced by lipopolysaccharide and muramyl dipeptide

Expression Analysis of Toll-Like Receptor2 in Bubaline Peripheral Blood Mononuclear Cells upon Stimulation by Bacillus Subtilis Cell Wall Peptidoglycan

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