Porphyrin derivatives inhibit tumor necrosis factor α-induced gene expression and reduce the expression and increase the cross-linked forms of cellular components of the nuclear factor κB signaling pathway.

ABSTRACT

The transcription factor nuclear factor κB (NF-κB) is activated by proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and Toll-like receptor (TLR) ligands. Screening of NPDepo chemical libraries identified porphyrin derivatives as anti-inflammatory compounds that strongly inhibited the up-regulation of intercellular adhesion molecule-1 (ICAM-1) expression induced by TNF-α, interleukin-1α, the TLR3 ligand, and TLR4 ligand in human umbilical vein endothelial cells. In the present study, the mechanisms of action of porphyrin derivatives were further elucidated using human lung adenocarcinoma A549 cells. Porphyrin derivatives, i.e., dimethyl-2,7,12,18-tetramethyl-3,8-di(1-methoxyethyl)-21H,23H-porphine-13,17-dipropionate (1) and pheophorbide a (2), inhibited TNF-α-induced ICAM-1 expression and decreased the TNF-α-induced transcription of ICAM-1, vascular cell adhesion molecule-1, and E-selectin genes. 1 and 2 reduced the expression of the NF-κB subunit RelA protein for 1 h, which was not rescued by the inhibition of proteasome- and lysosome-dependent protein degradation. In addition, 1 and 2 decreased the expression of multiple components of the TNF receptor 1 complex, and this was accompanied by the appearance of their cross-linked forms. As common components of the NF-κB signaling pathway, 1 and 2 also cross-linked the α, ß, and γ subunits of the inhibitor of NF-κB kinase complex and the NF-κB subunits RelA and p50. Cellular protein synthesis was prevented by 2, but not by 1. Therefore, the present results indicate that porphyrin derivative 1 reduced the expression and increased the cross-linked forms of cellular components required for the NF-κB signaling pathway without affecting global protein synthesis.