Differential cytokine induction by doses of lipopolysaccharide and monophosphoryl lipid A that result in equivalent early endotoxin tolerance

Abstract

The phenomenon of early endotoxin tolerance, which is induced by sublethal injection of lipopolysaccharide (LPS), results in a protracted period of hyporesponsiveness that is most profound at 3 to 4 days after injection and is marked by reduced cytokine production after a challenge injection of LPS. Early endotoxin tolerance is also induced by the nontoxic LPS derivative monophosphoryl lipid A (MPL), although much more of the monophosphoryl derivative is required to produce a state of tolerance equivalent to that evoked by LPS. In this study, equivalent tolerance-inducing doses of LPS and MPL were tested, and the levels of cytokines induced by LPS and MPL were compared. Although induced levels of colony-stimulating factor were comparable following doses of LPS and MPL that elicited an equivalent state of early endotoxin tolerance, levels of tumor necrosis factor, interleukin-6, and interferon were significantly lower in MPL-injected animals. These results suggest that the lowered toxicity of MPL may be related to its elicitation of significantly lower levels of potentially toxic intermediaries such as tumor necrosis factor, interferon, and interleukin-6.

Host responses induced by co‐infection with Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans in a murine model

“…This decrease in responses may be due to endotoxin suppression. It has been shown that sublethal injection of lipopolysaccharide results in a hyporesponsive period that was maximal at 3-4 days after injection (18). Alternatively, the reduced lymphoproliferative responses to mitogens may be due either to an enhanced susceptibility to infection or to a high degree of activation of defense mechanisms, as suggested by Brunner & Kroll (5).…”

Myocardial Protection by Monophosphoryl Lipid A: Potential Mechanisms

“…Similar to endotoxin, MLA can induce a variety of isotypes of cytokines (5,17,21,23,60), including tumor necrosis factor ␣ (TNF ␣ ), interleukin 6 (IL-6), interleukin 12 (IL-12), and interferon-␥ (INF-␥), that activate and recruit macrophages as well as inactivate suppressor T cell activity. This process eventually results in an enhancement of the immune response.…”

“…This process eventually results in an enhancement of the immune response. The immunostimulatory effects of MLA have been exploited to induce tolerance against bacterial infection (9) and endotoxemia (17,26) and as a prophylaxis against sepsis and septic shock (14). Astiz et al (2) demonstrated that MLA protected against sepsis caused by gram-negative as well as gram-positive bacterial strains.…”

“…It is well known that MLA stimulates cytokine release in various cell types (5,17,21,23,61), except in one rabbit study that showed a lack of TNF ␣ induction with a cardioprotective dose (35 g/kg, i.v.) of MLA (12).…”

“…It was extracted to reduce the associated toxicity while retaining the immunomodulatory properties of the parent endotoxin molecule. MLA has been shown to induce certain beneficial immunostimulatory effects such as macrophage stimulation, cytokine release, and a variety of other effects upon both humoral and cell-mediated immunological host defense response (3,17,21,27,36,61). The beneficial effects of MLA have been used in 1) inducing tolerance to endotoxemia in both laboratory animals and humans, 2) immunotherapy or immunoprophylaxis, 3) adjuvant for a number of vaccines, 4) inducing delayed protection against cerebral vasospasm caused by subarachnoid hemorrhage, and 5) delayed cardioprotection through complex mechanisms.…”