Heme is a prosthetic group in a large number of essential proteins that have a pivotal role in oxygen transport, storage and electron shuttling. High amounts of free heme are associated with pathological states. Recently, it has been suggested that activation of Toll-like receptor 4 (TLR4) is one of the ways in which the 'danger signal' of free heme is detected. Here, we examine the biochemical basis of the modulation of the TLR4 pathway by hemin (iron(III)-protoporphyrin IX) and its metabolic, oxidated derivative coprohemin (iron(III)-coproporphyrin I). High concentrations of hemin (50 μM) triggered TLR4-mediated IL-8 production in the human HEK293/TLR4 cell line in the absence of the co-receptors CD14 and MD-2; the latter an essential co-receptor for TLR4 activation by endotoxin. Hemin and endotoxin have additive effects when co-administrated to HEK/TLR4 cells, suggesting that hemin and endotoxin activate TLR4 by different mechanisms. Coprohemin, in contrast to hemin, is unable to trigger TLR4-dependent activation of HEK/TLR4 cells, but instead causes dose-dependent inhibition of endotoxin-stimulated IL-8 production. The inhibitory effect of coprohemin is paralleled by reduced delivery of endotoxin to MD-2 (-TLR4) that is necessary for activation of TLR4 by endotoxin. Thus, despite their similar chemical structure, hemin and coprohemin have very different effects on the TLR4 pathway, the former acting as a mild agonist of TLR4, the latter as an antagonist selectively targeting the endotoxin-MD-2 interaction. © SAGE Publications 2010.

Piazza, M., Damore, G., Costa, B., Gioannini, T., Weiss, J., & Peri, F. (2011). Hemin and a metabolic derivative coprohemin modulate the TLR4 pathway differently through different molecular targets. INNATE IMMUNITY, 17(3), 293-301 [10.1177/1753425910369020].

Hemin and a metabolic derivative coprohemin modulate the TLR4 pathway differently through different molecular targets

PIAZZA, MATTEO;COSTA, BARBARA SIMONA;PERI, FRANCESCO
2011

Abstract

Heme is a prosthetic group in a large number of essential proteins that have a pivotal role in oxygen transport, storage and electron shuttling. High amounts of free heme are associated with pathological states. Recently, it has been suggested that activation of Toll-like receptor 4 (TLR4) is one of the ways in which the 'danger signal' of free heme is detected. Here, we examine the biochemical basis of the modulation of the TLR4 pathway by hemin (iron(III)-protoporphyrin IX) and its metabolic, oxidated derivative coprohemin (iron(III)-coproporphyrin I). High concentrations of hemin (50 μM) triggered TLR4-mediated IL-8 production in the human HEK293/TLR4 cell line in the absence of the co-receptors CD14 and MD-2; the latter an essential co-receptor for TLR4 activation by endotoxin. Hemin and endotoxin have additive effects when co-administrated to HEK/TLR4 cells, suggesting that hemin and endotoxin activate TLR4 by different mechanisms. Coprohemin, in contrast to hemin, is unable to trigger TLR4-dependent activation of HEK/TLR4 cells, but instead causes dose-dependent inhibition of endotoxin-stimulated IL-8 production. The inhibitory effect of coprohemin is paralleled by reduced delivery of endotoxin to MD-2 (-TLR4) that is necessary for activation of TLR4 by endotoxin. Thus, despite their similar chemical structure, hemin and coprohemin have very different effects on the TLR4 pathway, the former acting as a mild agonist of TLR4, the latter as an antagonist selectively targeting the endotoxin-MD-2 interaction. © SAGE Publications 2010.
Articolo in rivista - Articolo scientifico
Scientifica
TLR4; MD-2; heme; hemin; coprohemin
English
Piazza, M., Damore, G., Costa, B., Gioannini, T., Weiss, J., & Peri, F. (2011). Hemin and a metabolic derivative coprohemin modulate the TLR4 pathway differently through different molecular targets. INNATE IMMUNITY, 17(3), 293-301 [10.1177/1753425910369020].
Piazza, M; Damore, G; Costa, B; Gioannini, T; Weiss, J; Peri, F
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10281/18865
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