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Am J Physiol Cell Physiol (July 2, 2003). doi:10.1152/ajpcell.00164.2003
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Submitted on April 25, 2003
Accepted on June 25, 2003

Methemoglobin is a potent activator of endothelial cells by stimulating IL-6 and IL-8 production and E-selectin membrane expression

Xueying Liu1 and Zoltan Spolarics2*

1 Cell Biology and Molecular Medicine, UMDNJ-New Jersey Medical School, Newark, NJ, USA
2 Surgery, UMDNJ-New Jersey Medical School, Newark, NJ, USA

* To whom correspondence should be addressed. E-mail: spolaric{at}umdnj.edu.

Infection and injury are frequently accompanied by hemolysis. Endothelial cells are direct targets of free hemoglobin (Hb) or its oxidative derivatives, including methemoglobin (MHb) and hemin. This study tested whether hemoglobin or its derivatives alter the chemokine (IL-8) and cytokine (IL-6) production, and the membrane expression of cell adhesion molecule (E-selectin) in human umbilical vein endothelial cells (passage 2 to 4, HUVEC). E-selectin membrane content and IL-6 and IL-8 release were quantified by ELISA; cellular mRNA levels were determined by RT-PCR. MHb in vitro resulted in a dose- (1-50µM) and time-dependent (2-16h) increase in E-selectin membrane content, as well as, IL-6 and IL-8 release in HUVEC. The stimulatory effect of MHb (12 µM) on E-selectin membrane expression and IL-6 and IL-8 release was similar to that produced after TNF-{alpha} (5ng/ml) or IL-1{beta} (0.25ng/ml) treatments. In contrast, Hb or hemin had no effects. As expected, MHb, Hb, as well as hemin markedly induced heme oxygenase-1 expression in HUVEC. Haptoglobin, cytochalasin-D and actinomycin inhibited the MHb-induced responses, whereas, Zn-protoporphyrin IX (heme oxygenase inhibitor) or desferroxamine (iron chelator) did not inhibit MHb-induced responses. MHb also increased cellular mRNA levels of E-selectin, IL-6 and IL-8. MHb treatment activated cellular NF{kappa}B, and NF{kappa}B inhibitors, N-acetyl-cysteine, SN-50 and CAPE inhibited the MHb-induced responses. These data indicate that MHb is a potent activator of endothelial cells through NF{kappa}B-mediated up-regulation of cell adhesion molecule expression, and chemokine and cytokine production. MHb-induced endothelial cell activation may have clinical significance following infections, hemolysis or methemoglobinemia.




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