title: Iron chelator triggers inflammatory signals in human intestinal epithelial cells: involvement of p38 and extracellular signal-regulated kinase signaling pathways.
abstract: Competition for cellular iron (Fe) is a vital component of the interaction between host and pathogen. Most bacteria have an obligate requirement for Fe to sustain infection, growth, and survival in host. To obtain iron required for growth, many bacteria secrete iron chelators (siderophores). This study was undertaken to test whether a bacterial siderophore, deferoxamine (DFO), could trigger inflammatory signals in human intestinal epithelial cells as a single stimulus. Incubation of human intestinal epithelial HT-29 cells with DFO increased the expression of IL-8 mRNA, as well as the release of IL-8 protein. The signal transduction study revealed that both p38 and extracellular signal-regulated kinase-1/2 were significantly activated in response to DFO. Accordingly, the selective inhibitors for both kinases, either alone or in combination, completely abolished DFO-induced IL-8 secretion, indicating an importance of mitogen-activated protein kinases pathway. These proinflammatory effects of DFO were, in large part, mediated by activation of Na(+)/H(+) exchangers, because selective blockade of Na(+)/H(+) exchangers prevented the DFO-induced IL-8 production. Interestingly, however, DFO neither induced NF-kappaB activation by itself nor affected IL-1beta- or TNF-alpha-mediated NF-kappaB activation, suggesting a NF-kappaB-independent mechanism in DFO-induced IL-8 production. Global gene expression profiling revealed that DFO significantly up-regulates inflammation-related genes including proinflammatory genes, and that many of those genes are down-modulated by the selective mitogen-activated protein kinase inhibitors. Collectively, these results demonstrate that, in addition to bacterial products or cell wall components, direct chelation of host Fe by infected bacteria may also contribute to the evocation of host inflammatory responses.
authors.affiliation: Department of Microbiology and Immunology and Digestive Disease Research Institute, School of Medicine, Wonkwang University, Iksan, Chonbuk, Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Choi
authors.forename: Eun-Cheol
authors.initials: EC
authors.lastname: Kim
authors.forename: Hyun-Mee
authors.initials: HM
authors.lastname: Oh
authors.forename: Soonhag
authors.initials: S
authors.lastname: Kim
authors.forename: Hyun-Ju
authors.initials: HJ
authors.lastname: Lee
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Cho
authors.forename: Kwon-Ha
authors.initials: KH
authors.lastname: Yoon
authors.forename: Eun-A
authors.initials: EA
authors.lastname: Kim
authors.forename: Weon-Cheol
authors.initials: WC
authors.lastname: Han
authors.forename: Suck-Chei
authors.initials: SC
authors.lastname: Choi
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Hwang
authors.forename: Chan
authors.initials: C
authors.lastname: Park
authors.forename: Berm-Seok
authors.initials: BS
authors.lastname: Oh
authors.forename: Youngyoul
authors.initials: Y
authors.lastname: Kim
authors.forename: Ku-Chan
authors.initials: KC
authors.lastname: Kimm
authors.forename: Kie-In
authors.initials: KI
authors.lastname: Park
authors.forename: Hun-Taeg
authors.initials: HT
authors.lastname: Chung
authors.forename: Chang-Duk
authors.initials: CD
authors.lastname: Jun
mesh_terms: D003676:Deferoxamine / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D016209:Interleukin-8; D007502:Iron Chelating Agents; D016328:NF-kappa B; D012333:RNA, Messenger; D017923:Sodium-Hydrogen Exchangers; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003676:Deferoxamine