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

Abstract

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 ...

Engagement of NOD2 has a dual effect on proIL‐1β mRNA transcription and secretion of bioactive IL‐1β

“…Indeed, the synergistic production of IL-1b by MDP and LPS is caspase-1dependent, and not regulated at transcriptional level. However, in line with other studies, we show that the mechanism of synergy for TNF-a is exerted at a transcriptional level [40].…”

“…Indeed, the synergistic production of IL-1b by MDP and LPS is caspase-1dependent, and not regulated at transcriptional level. However, in line with other studies, we show that the mechanism of synergy for TNF-a is exerted at a transcriptional level [40].In conclusion, we demonstrate that NOD2 is nonredundant for both the production of IL-1b mRNA and the IL-1b release from the activated cells. In addition, indirect data supports a role for NOD2 in the activation of caspase-1 in human MNC after stimulation with MDP.…”

TIR, CARD and PYRIN: three domains for an antimicrobial triad

“…The following observations could account for the actual TLR/Nod synergy: (i) LPS stimulation upregulates Rip2 expression in murine macrophages, 80 (ii) TAK1, a molecule implicated in the canonical MyD88-dependent TLR signaling, has also been shown to participate in the Nod2 pathway, 93 (iii) MDP stimulation upregulates MyD88 expression, 133 (iv) MDP-stimulated macrophages induce a significant upregulation of TNF mRNA, and LPS costimulation efficiently enhances TNF mRNA translation and release. 134 It is possible that all the above observations contribute, in part, to the synergistic effect of Nods on TLR signaling, and that not a single mechanism is responsible for the global effect.…”

Potential adjuvantic properties of innate immune stimuli

“…[238][239][240][241][242] Nod1 and Nod2 activation also drive adaptive immune responses. Kobayashi et al have shown that Nod2 mediates adjuvant activity through the production of IgG1-type antibodies to T-cell-dependent antigens.…”