Iron chelator induces MIP-alpha/CCL20 in human intestinal epithelial cells: implication for triggering mucosal adaptive immunity.
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.
Lee
Hyun-Ju
HJ
Department of Physiology, Kyungpook National University School of Medicine, Daegu 700-422, Korea.
Choi
Suck-Chei
SC
Choi
Eun-Young
EY
Lee
Moo-Hyung
MH
Seo
Geom-Seog
GS
Kim
Eun-Cheol
EC
Yang
Bong-Joon
BJ
Lee
Myeung-Su
MS
Shin
Yong-Il
YI
Park
Kie-In
KI
Jun
Chang-Duk
CD
D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054399:Receptors, CCR6; D019707:Receptors, Chemokine / Q000378:metabolism
C108355:CCL20 protein, human; C106311:CCR6 protein, human; D054418:Chemokine CCL20; D019742:Chemokines, CC; D007502:Iron Chelating Agents; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D054399:Receptors, CCR6; D019707:Receptors, Chemokine; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D003676:Deferoxamine; D002118:Calcium