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Infection and Immunity, June 2007, p. 3160-3168, Vol. 75, No. 6
0019-9567/07/$08.00+0     doi:10.1128/IAI.01719-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Interleukin-8 Secretion in Response to Aferric Enterobactin Is Potentiated by Siderocalin{triangledown}

Aaron L. Nelson,1 Adam J. Ratner,1 Jonathan Barasch,2 and Jeffrey N. Weiser1,3*

Departments of Microbiology,1 Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104,3 Division of Nephrology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 100322

Received 26 October 2006/ Returned for modification 17 December 2006/ Accepted 26 March 2007

Siderophores are low-molecular-weight iron chelators secreted by microbes to obtain iron under deprivation. We hypothesized that the catecholate siderophore enterobactin, produced by Enterobacteriaceae, serves as a proinflammatory signal for respiratory epithelial cells. Respiratory tract responses were explored, since at this site siderocalin, an enterobactin-binding mammalian gene product, is expressed inducibly at high levels and enterobactin-secreting respiratory flora is rare, suggesting selection against a dependence on enterobactin. Addition of aferric, but not iron-saturated, enterobactin elicits a dose-dependent increase in secretion of the proinflammatory chemokine interleukin-8 by human respiratory epithelial cells in culture. This response to purified enterobactin is potentiated by recombinant siderocalin at physiologically relevant concentrations. Conditioned media from genetically modified Escherichia coli strains expressing various levels of enterobactin induce an enterobactin-mediated proinflammatory response. Siderocalin has been shown to deliver enterobactin to other mammalian cell types, exogenously supplied siderocalin can be detected within epithelial cells, and siderocalin increases delivery of enterobactin to the intracellular compartment. Although many siderophores perturb labile cellular iron pools, only enterobactin elicits interleukin-8 secretion, suggesting that iron chelation is necessary but not sufficient. Thus, aferric enterobactin may be a proinflammatory signal for respiratory epithelial cells, permitting detection of microbial communities that have disturbed local iron homeostasis, and siderocalin expression by the host amplifies this signal. This may be a novel mechanism for the mucosa to respond to metabolic signals of expanding microbial communities.

* Corresponding author. Mailing address: 402A Johnson Pavilion, Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104-6076. Phone: (215) 573-3511. Fax: (215) 898-9557. E-mail: weiser{at}mail.med.upenn.edu

{triangledown} Published ahead of print on 9 April 2007.

Editor: J. B. Bliska

Infection and Immunity, June 2007, p. 3160-3168, Vol. 75, No. 6
0019-9567/07/$08.00+0     doi:10.1128/IAI.01719-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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