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TRANSLATIONAL PHYSIOLOGY

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

Departments of ¹Surgery, ²Cellular and Integrative Physiology, ³Pulmonary and Critical Care Medicine and ⁴Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 27 October 2006 ; accepted in final form 29 December 2006

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- 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- while increasing VEGF and HGF therefore have theoretical appeal. We hypothesized that 1) fetal human intestinal epithelial cells acutely produce increased IL-6, TNF-, 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-, 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- 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- production. Furthermore, chelator-induced intestinal epithelial cell cytokine expression depends on p38, ERK, and JNK MAPK pathways.

intestinal ischemia; inflammation; mitogen-activated protein kinase signaling; interleukin-6; vascular endothelial growth factor; hepatocyte growth factor; extracellular signal-regulated kinase; c-Jun NH₂-terminal kinase