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 microm) 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.
Piazza, M., Damore, G., Costa, B.S., Gioannini, T.L., Weiss, J.P., & 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].
|Citazione:||Piazza, M., Damore, G., Costa, B.S., Gioannini, T.L., Weiss, J.P., & 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].|
|Tipo:||Articolo in rivista - Articolo scientifico|
|Carattere della pubblicazione:||Scientifica|
|Presenza di un coautore afferente ad Istituzioni straniere:||Si|
|Titolo:||Hemin and a metabolic derivative coprohemin modulate the TLR4 pathway differently through different molecular targets|
|Autori:||Piazza, M; Damore, G; Costa, BS; Gioannini, TL; Weiss, JP; Peri, F|
|Data di pubblicazione:||2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1177/1753425910369020|
|Appare nelle tipologie:||01 - Articolo su rivista|