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Clinical and Diagnostic Laboratory Immunology, March 2005, p. 436-446, Vol. 12, No. 3
1071-412X/05/$08.00+0     doi:10.1128/CDLI.12.3.436-446.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Interleukin-18 Primes the Oxidative Burst of Neutrophils in Response to Formyl-Peptides: Role of Cytochrome b558 Translocation and N-Formyl Peptide Receptor Endocytosis

Carole Elbim,1,2 Cécile Guichard,1 Pham M. C. Dang,1 Michèle Fay,1 Eric Pedruzzi,1 Hélène Demur,2 Cécile Pouzet,3 Jamel El Benna,1 and Marie-Anne Gougerot-Pocidalo1,2*

Institut National de la Santé et de la Recherche Médicale, Unité 479,1 Institut National de la Santé et de la Recherche Médicale, IFR 02, Faculté Xavier Bichat,3 Service d'Immunologie et d'Hématologie, Centre Hospitalo-Universitaire Xavier Bichat, Paris, France2

Received 13 October 2004/ Returned for modification 17 November 2004/ Accepted 21 December 2004

Using flow cytometry, we observed that interleukin-18 (IL-18) primed human neutrophils (PMNs) in whole blood to produce superoxide anion (O2°–) in response to N-formyl peptide (fMLP) stimulation, whereas IL-18 alone had no significant effect. In contrast to tumor necrosis factor alpha (TNF-{alpha}), which is a cytokine known to strongly prime O2°– production, IL-18 did not induce either p47phox phosphorylation or its translocation from the cytosol to the plasma membrane. However, IL-18 increased PMN degranulation, as shown by increased levels of cytochrome b558 and CD11b expression at the PMN surface. Moreover, addition of IL-18 to whole blood for 45 min reduced the ability of PMNs to bind to fMLP, suggesting endocytosis of fMLP receptors, as visualized by confocal microscopy. 2,3-Butanedione 2-monoxime, which inhibits endosomal recycling of plasma membrane components back to the cell surface, concomitantly accentuated the diminution of fMLP binding at the PMN surface and increased IL-18 priming of O2°– production by PMNs in response to fMLP. This suggests that fMLP receptor endocytosis could account, at least in part, for the priming of O2°– production. In addition, genistein, a tyrosine kinase inhibitor, and SB203580, a p38 mitogen-activated protein kinase (p38MAPK) inhibitor, completely reversed the decreased level of fMLP binding and increased the level of CD11b expression after IL-18 treatment. Flow cytometric analysis of intact PMNs in whole blood showed that IL-18 increased p38MAPK phosphorylation and tyrosine phosphorylation. In particular, IL-18 induced phosphorylation of focal adhesion kinase (p125FAK), which has been implicated in cytoskeleton reorganization. Taken together, our findings suggest several mechanisms that are likely to regulate cytokine-induced priming of the oxidative burst in PMNs in their blood environment.

* Corresponding author. Mailing address: Unité INSERM U479, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75877 Paris Cedex 18, France. Phone: (33) 1 44 85 62 10. Fax: (33) 1 44 85 62 07. E-mail: pocidalo{at}bichat.inserm.fr.

Clinical and Diagnostic Laboratory Immunology, March 2005, p. 436-446, Vol. 12, No. 3
1071-412X/05/$08.00+0     doi:10.1128/CDLI.12.3.436-446.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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