Abstract
A previous report by this laboratory demonstrated that bacterial iron chelator (siderophore) triggers inflammatory signals, including the production of CXC chemokine IL-8, in human intestinal epithelial cells (IECs). Microarray-based gene expression profiling revealed that iron chelator also induces macrophage inflammatory protein 3 alpha (MIP-3alpha)/CC chemokine-ligand 20 (CCL20). As CCL20 is chemotactic for the cells involved in host adaptive immunity, this suggests that iron chelator may stimulate IECs to have the capacity to link mucosal innate and adaptive immunity. The basal medium from iron chelator deferoxamine (DFO)-treated HT-29 monolayers was as chemotactic as recombinant human CCL20 at equivalent concentrations to attract CCR6(+) cells. The increase of CCL20 protein secretion appeared to correspond to that of CCL20 mRNA levels, as determined by real-time quantitative RT-PCR. The efficacy of DFO at inducing CCL20 mRNA was also observed in human PBMCs and in THP-1 cells, but not in human umbilical vein endothelial cells. Interestingly, unlike other proinflammatory cytokines, such as TNF-alpha and IL-1beta, a time-dependent experiment revealed that DFO slowly induces CCL20, suggesting a novel mechanism of action. A pharmacologic study also revealed that multiple signaling pathways are differentially involved in CCL20 production by DFO, while some of those pathways are not involved in TNF-alpha-induced CCL20 production. Collectively, these results demonstrate that, in addition to some bacterial products known to induce host adaptive immune responses, direct chelation of host iron by infected bacteria may also contribute to the initiation of host adaptive immunity in the intestinal mucosa.
Highlights
Iron is a critical nutritional element, essential for a great variety of important biological processes, including cell growth and differentiation, electron transfer reactions, and oxygen transport, activation, and detoxification (Crichton et al, 1992)
We documented for the first time that iron chelator triggers inflammatory signals, including the production of CXC chemokine IL-8, in human intestinal epithelial cells (IECs) even in the absence of conventional immuno-stimulatory/inflammatory stimuli
Molecules involved in iron uptake and transport may be receptors or channels and siderophores (Greek for ‘iron bearers’), which are high-affinity specific iron-binding molecules that are shuttled to the environment to catch iron
Summary
Iron is a critical nutritional element, essential for a great variety of important biological processes, including cell growth and differentiation, electron transfer reactions, and oxygen transport, activation, and detoxification (Crichton et al, 1992). Maintaining iron availability for cellular metabolic and growth requirements is critical to the survival of both prokaryotes and eukaryotes. Iron is a central element in the regulation of immune function. A sufficient supply with iron is of pivotal importance for immuno-surveillence because of iron’s growth-promoting role for immune cells and its interference with cell-mediated immune effector pathways and cytokine activities (Brieva et al.,1984; Bierer et al, 1990; Golding et al, 1995; Weiss et al, 1995; Gray et al, 2002; Lee et al, 2004). Iron is directly involved in cytotoxic immune defense mechanisms in which it is needed to catalyze the formation of the hydroxyl radical
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