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Infection and Immunity, March 1999, p. 1297-1302, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Role of the Extracellular Signal-Regulated Protein Kinase Cascade in Human Neutrophil Killing of Staphylococcus aureus and Candida albicans and in Migration

Charles S. T. Hii,1,* Kathryn Stacey,1 Nahid Moghaddami,1 Andrew W. Murray,2 and Antonio Ferrante1,3

Department of Immunopathology, Women's and Children's Hospital, North Adelaide,1 Department of Pediatrics, University of Adelaide, Adelaide,3 and School of Biological Sciences, Flinders University of South Australia, Bedford Park,2 South Australia, Australia

Received 22 June 1998/Returned for modification 29 July 1998/Accepted 18 November 1998

Killing of Staphylococcus aureus and Candida albicans by neutrophils involves adherence of the microorganisms, phagocytosis, and a collaborative action of oxygen reactive species and components of the granules. While a number of intracellular signalling pathways have been proposed to regulate neutrophil responses, the extent to which each pathway contributes to the killing of S. aureus and C. albicans has not been clearly defined. We have therefore examined the effect of blocking one such pathway, the extracellular signal-regulated protein kinase (ERK) cascade, using the specific inhibitor of the mitogen-activated protein kinase/ERK kinase, PD98059, on the ability of human neutrophils to kill S. aureus and C. albicans. Our data demonstrate the presence of ERK2 and a 43-kDa form of ERK but not ERK1 in human neutrophils. Upon stimulation with formyl methionyl leucyl phenylalanine (fMLP), the activities of both ERK2 and the 43-kDa form were stimulated. Despite abrogating the activity of both ERK forms, PD98059 only slightly reduced the ability of neutrophils to kill S. aureus or C. albicans. This is consistent with our finding that PD98059 had no effect on neutrophil adherence or degranulation, although pretreatment of neutrophils with PD98059 inhibited fMLP-stimulated superoxide production by 50%, suggesting that a change in superoxide production per se is not strictly correlated with microbicidal activity. However, fMLP-stimulated chemokinesis was markedly inhibited, while random migration and fMLP-stimulated chemotaxis were partially inhibited, by PD98059. These data demonstrate, for the first time, that the ERK cascade plays only a minor role in the microbicidal activity of neutrophils and that the ERK cascade is involved primarily in regulating neutrophil migration in response to fMLP.

* Corresponding author. Mailing address: Department of Immunopathology, Women's and Children's Hospital, 72 King William Rd., North Adelaide, South Australia 5006, Australia. Phone: 08-8204-6293. Fax: 08-8204-6046. E-mail: chii{at}medicine.adelaide.edu.au.

Infection and Immunity, March 1999, p. 1297-1302, Vol. 67, No. 3
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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