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(Journal of Leukocyte Biology. 2001;70:381-385.)
© 2001 by Society for Leukocyte Biology

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 and L-J. Eales-Reynolds

School of Biomedical and Life Sciences, University of Surrey, Guildford, UK;
^* New York Medical College, Valhalla, New York; and
St. Vincent’s Hospital, Harrison, New York

Correspondence: Dr. L-J. Eales-Reynolds, Senior Lecturer in Immunology, School of Biomedical and Life Sciences, University of Surrey, Guildford, GU2 7XH UK. E-mail: L.Reynolds{at}surrey.ac.uk

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 lipopolysacchardies (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 IB, which occurs when human monocytes are cultured with LPS. From our results, we propose a model for the reduced toxicity of MPL.

Key Words: mononuclear phagocytes • lipopolysaccharide • IB • adjuvants

This article has been cited by other articles:

				T. Rustam, S. McClean, J. Newcombe, J. McFadden, and L.-J. Eales-Reynolds Reduced toxicity of lipo-oligosaccharide from a phoP mutant of Neisseria meningitidis: an in vitro demonstration Innate Immunity, February 1, 2006; 12(1): 39 - 46. [Abstract] [PDF]

				S. Klaus, K. H Staubach, M. Heringlake, J. Gliemroth, P. Schmucker, and L. Bahlmann Tissue metabolism during endotoxin shock after pretreatment with monophosphoryl lipid A Cardiovasc Res, July 1, 2003; 59(1): 105 - 112. [Abstract] [Full Text] [PDF]