title: Iron chelation acutely stimulates fetal human intestinal cell production of IL-6 and VEGF while decreasing HGF: the roles of p38, ERK, and JNK MAPK signaling.
abstract: Bacteria have developed mechanisms to sequester host iron via chelators such as deferoxamine (DFO). Interestingly, DFO has been shown to stimulate acute intestinal epithelial cell inflammatory cytokine production in the absence of bacteria; however, this mechanism has not been elucidated. Intestinal epithelial cell production of IL-6 and TNF-alpha is elevated in various gastrointestinal pathologies, including acute intestinal ischemia. Similarly, VEGF and HGF are essential to intestinal epithelial cell integrity. Therapeutic strategies that decrease IL-6 and TNF-alpha while increasing VEGF and HGF therefore have theoretical appeal. We hypothesized that 1) fetal human intestinal epithelial cells acutely produce increased IL-6, TNF-alpha, VEGF, and HGF during iron chelation and 2) the MAPK pathway mediates these effects. Fetal human intestinal epithelial cells were stimulated by iron chelation (1 mM DFO) with and without p38 MAPK, ERK, or JNK inhibition. Supernatants were harvested after 24 h of incubation, and IL-6, TNF-alpha, VEGF, and HGF levels were quantified by ELISA. Activation of MAPK pathways was confirmed by Western blot analysis. DFO stimulation resulted in a significant increase in epithelial cell IL-6 and VEGF production while yielding a decrease in HGF production (P<0.05). Unexpectedly, TNF-alpha was not detectable. p38 MAPK, ERK, and JNK inhibition significantly decreased IL-6, VEGF, and HGF production (P<0.05). In conclusion, DFO acutely increases fetal human intestinal epithelial cell IL-6 and VEGF expression while causing an unexpected decrease in HGF expression and no detectable TNF-alpha production. Furthermore, chelator-induced intestinal epithelial cell cytokine expression depends on p38, ERK, and JNK MAPK pathways.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Troy A
authors.initials: TA
authors.lastname: Markel
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crisostomo
authors.forename: Meijing
authors.initials: M
authors.lastname: Wang
authors.forename: Christine M
authors.initials: CM
authors.lastname: Herring
authors.forename: Tim
authors.initials: T
authors.lastname: Lahm
authors.forename: Kirstan K
authors.initials: KK
authors.lastname: Meldrum
authors.forename: Keith D
authors.initials: KD
authors.lastname: Lillemoe
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Rescorla
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D015153:Blotting, Western; D002460:Cell Line; D003676:Deferoxamine / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005333:Fetus; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D007502:Iron Chelating Agents; D047428:Protein Kinase Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D003676:Deferoxamine