Monophosphoryl lipid A stimulated up-regulation of reactive oxygen intermediates in human monocytes in vitro

D. C. Saha, R. S. Barua, M. E. Astiz, E. C. Rackow, L. J. Eales-Reynolds

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

The production of reactive oxygen and nitrogen intermediates is a common response to infectious challenge in vivo. These agents have been implicated in the modulation of cytokine responses and are produced in large amounts in response to endotoxins produced by a number of infectious agents. The antigen-presenting cell activation caused by these lipopolysaccharides (LPS) has been exploited in the use of these agents as adjuvants. In recent years, less-toxic derivatives have been sought. One such agent, monophosphoryl lipid A (MPL), has been used increasingly in vivo as an adjuvant and as a modulator of the inflammatory process. It is known that this agent modulates the inflammatory response and cytokine production. In addition, we have shown its effect on the production of reactive nitrogen intermediates. In this paper, we show that MPL stimulates the release of high levels of superoxide (O2-) and hydrogen peroxide (H2O2), the latter being greater than that seen with LPS and appearing to be related to the inability of MPL to stimulate catalase activity. When cells were pretreated with LPS or MPL and subsequently challenged with LPS, the production of O2- and H2O2 was inhibited significantly by LPS and MPL. The concentration of MPL required to induce significant hyporesponsiveness to subsequent LPS challenge was 10 times lower than that of LPS. Hyporesponsiveness was greatest when induced by 10 μg/ml MPL, the same concentration that induced the maximum release of H2O2 in primary stimulation. In addition, we have shown that following MPL pretreatment, LPS stimulation does not cause the loss of cytoplasmic IκBα, which occurs when human monocytes are cultured with LPS. From our results, we propose a model for the reduced toxicity of MPL.

Original languageEnglish (US)
Pages (from-to)381-385
Number of pages5
JournalJournal of Leukocyte Biology
Volume70
Issue number3
StatePublished - Sep 18 2001
Externally publishedYes

Keywords

  • Adjuvants
  • IκBα
  • Lipopolysaccharide
  • Mononuclear phagocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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