Iron Chelator Triggers Inflammatory Signals in Human Intestinal Epithelial Cells: Involvement of p38 and Extracellular Signal-Regulated Kinase Signaling Pathways

Choi, Eun‐Young; Kim, Eun-Cheol; Oh, Hyun-Mee; Kim, Soonhag; Lee, Hyunju; Cho, Eunyoung; Yoon, Kwon‐Ha; Kim, Eun-A; Han, Weon‐Cheol; Choi, Suck-Chei; Hwang, Joo-Yeon; Park, Chan; Oh, Bermseok; Kim, Young-Youl; Kimm, Kuchan; Park, Kie‐In; Chung, Hun‐Taeg; Jun, Chang‐Duk

doi:10.4049/jimmunol.172.11.7069

Cited by 67 publications

(83 citation statements)

References 53 publications

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“…In addition, enterobactin, independent of iron chelation, and desferrioxamine are cytotoxic for proliferating T cells (6,49). However, other groups using desferrioxamine have found stimulatory effects on inflammatory cytokine production by intestinal and U937 cell lines (29,57,91). Pyochelin, which resembles Ybt structurally, can generate hydroxyl radicals and, under the appropriate conditions, damage pulmonary endothelial and epithelial cells (23,24,30).…”

Section: Discussionmentioning

confidence: 99%

The Yersiniabactin Transport System Is Critical for the Pathogenesis of Bubonic and Pneumonic Plague

et al. 2010

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Iron acquisition from the host is an important step in the pathogenic process. While Yersinia pestis has multiple iron transporters, the yersiniabactin (Ybt) siderophore-dependent system plays a major role in iron acquisition in vitro and in vivo. In this study, we determined that the Ybt system is required for the use of iron bound by transferrin and lactoferrin and examined the importance of the Ybt system for virulence in mouse models of bubonic and pneumonic plague. Y. pestis mutants unable to either transport Ybt or synthesize the siderophore were both essentially avirulent via subcutaneous injection (bubonic plague model). Surprisingly, via intranasal instillation (pneumonic plague model), we saw a difference in the virulence of Ybt biosynthetic and transport mutants. Ybt biosynthetic mutants displayed an ϳ24-fold-higher 50% lethal dose (LD 50 ) than transport mutants. In contrast, under iron-restricted conditions in vitro, a Ybt transport mutant had a more severe growth defect than the Ybt biosynthetic mutant. Finally, a ⌬pgm mutant had a greater loss of virulence than the Ybt biosynthetic mutant, indicating that the 102-kb pgm locus encodes a virulence factor, in addition to Ybt, that plays a role in the pathogenesis of pneumonic plague.Nearly all organisms require trace amounts of iron. Pathogens must overcome host iron-and heme-binding proteins to cause an infection and disease. The importance of iron acquisition mechanisms has been demonstrated in a number of bacterial pathogens (14,15,27,32,85). Yersinia pestis, the causative agent of plague, has a number of proven and putative iron and heme transport systems. Of these systems, the yersiniabactin (Ybt) siderophore-dependent iron transport system plays a major role in the virulence of bubonic plague in mice (7,8,38,76,79).All identified genes required for the regulation, synthesis, and transport of Ybt, except for ybtD, are carried within a high-pathogenicity island (HPI) that has been spread among enteric pathogens but is essentially identical in the pathogenic yersiniae (13,59,79). In Y. pestis, the ϳ36-kb HPI is located within the 102-kb pgm locus; the entire pgm locus undergoes spontaneous deletion in vitro at a frequency of about 10 Ϫ5 (25, 39, 62). The Ybt system produces a siderophore composed of one salicylate, one thiazoline, and two thiazolidine rings via a nonribosomal peptide/polyketide synthesis mechanism involving high-molecular-weight protein 1 (HMWP1), HMWP2, YbtD, YbtT, YbtE, YbtU, and YbtS (76, 79, 94). The formation constant of this siderophore with ferric iron is 4 ϫ 10 36 , and the crystal structure of the ferric complex has been solved (68, 78).Iron from the Ybt-Fe complex is transported into the cell via the TonB-dependent outer membrane (OM) receptor Psn (which is also required for sensitivity to the bacteriocin pesticin) and an ABC transporter consisting of two inner membrane (IM), fused-function permease/ATP-binding proteins, YbtP and YbtQ. A mutation in any of these three genes prevents Ybt-dependent uptake of iron but does ...

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Section: Discussionmentioning

confidence: 99%

The Yersiniabactin Transport System Is Critical for the Pathogenesis of Bubonic and Pneumonic Plague

et al. 2010

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“…Alternatively, it may be that siderocalin potentiation is due to stabilization of bound enterobactin molecules, preventing degradation, and effectively increasing enterobactin concentration over time. Nor is it clear why A549 cells do not secrete IL-8 in response to deferrioxamine, in contrast to HT29 intestinal epithelial cells (9), although other groups have shown differential cytokine responses to treatment of human cells with different siderophores (9,16,22). Future studies will examine the cellular mechanisms of the response to enterobactin and enterobactin-siderocalin complex and may clarify the relative contributions of the bacteriostatic and proinflammatory properties of siderocalin.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been proposed that iron acquisition by siderophores could serve to modulate the inflammatory responses of host animals (9,16). We sought to test this question in an experimental model of the human respiratory tract by exposing the epithelial cell line A549 to a variety of microbial siderophores.…”

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confidence: 99%

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

Nelson¹,

Ratner²,

Barasch

et al. 2007

Infect Immun

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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.

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“…Furthermore, P. aeruginosa pyochelin is implicated, by virtue of being a catalyst for generating a hydroxyl radical, as a mediator of tissue damage (15). Finally, several different siderophores are capable of directly altering, at least in vitro, the viability and function of cells of the immune system, including T cells and macrophages (2,3,20,47,54,95). Thus, future examination of the role of legiobactin in infection needs to consider the variety of ways that siderophores can act.…”

Section: Discussionmentioning

confidence: 99%

Purification of Legiobactin and Importance of This Siderophore in Lung Infection byLegionella pneumophila

Allard

Dao

Sanjeevaiah³

et al. 2009

Infect Immun

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When cultured in a low-iron medium, Legionella pneumophila secretes a siderophore (legiobactin) that is both reactive in the chrome azurol S (CAS) assay and capable of stimulating the growth of iron-starved legionellae. Using anion-exchange high-pressure liquid chromatography (HPLC), we purified legiobactin from culture supernatants of a virulent strain of L. pneumophila. In the process, we detected the ferrated form of legiobactin as well as other CAS-reactive substances. Purified legiobactin had a yellow-gold color and absorbed primarily from 220 nm and below. In accordance, nuclear magnetic resonance spectroscopy revealed that legiobactin lacks aromatic carbons, and among the 13 aliphatics present, there were 3 carbonyls. When examined by HPLC, supernatants from L. pneumophila mutants inactivated for lbtA and lbtB completely lacked legiobactin, indicating that the LbtA and LbtB proteins are absolutely required for siderophore activity. Independently derived lbtA mutants, but not a complemented derivative, displayed a reduced ability to infect the lungs of A/J mice after intratracheal inoculation, indicating that legiobactin is required for optimal intrapulmonary survival by L. pneumophila. This defect, however, was not evident when the lbtA mutant and its parental strain were coinoculated into the lung, indicating that legiobactin secreted by the wild type can promote growth of the mutant in trans. Legiobactin mutants grew normally in murine lung macrophages and alveolar epithelial cells, suggesting that legiobactin promotes something other than intracellular infection of resident lung cells. Overall, these data represent the first documentation of a role for siderophore expression in the virulence of L. pneumophila.

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Iron Chelator Triggers Inflammatory Signals in Human Intestinal Epithelial Cells: Involvement of p38 and Extracellular Signal-Regulated Kinase Signaling Pathways

Cited by 67 publications

References 53 publications

The Yersiniabactin Transport System Is Critical for the Pathogenesis of Bubonic and Pneumonic Plague

The Yersiniabactin Transport System Is Critical for the Pathogenesis of Bubonic and Pneumonic Plague

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

Purification of Legiobactin and Importance of This Siderophore in Lung Infection byLegionella pneumophila

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