Bacterial Lipopolysaccharide Activates Nuclear Factor-κB through Interleukin-1 Signaling Mediators in Cultured Human Dermal Endothelial Cells and Mononuclear Phagocytes

• Published in: The Journal of biological chemistry 1999-03, Vol.274 (12), p.7611-7614
• Main Authors: Zhang, Frank X., Kirschning, Carsten J., Mancinelli, Roberta, Xu, Xiao-Ping, Jin, Yiping, Faure, Emmanuelle, Mantovani, Alberto, Rothe, Mike, Muzio, Marta, Arditi, Moshe
• Format: Article
• Language: English
• ISSN: 0021-9258
• DOI: 10.1074/jbc.274.12.7611

Bacterial lipopolysaccharide (LPS)-mediated immune responses, including activation of monocytes macrophages, and endothelial cells, play an important role in the pathogenesis of Gram-negative bacteria-induced sepsis syndrome. Activation of NF- Kappa B is thought to be required for cytokine release from LPS-responsive cells, a critical step for endotoxic effects. Here we investigated the role and involvement of interleukin-1 (IL-1) and tumor necrosis factor (TNF- alpha ) signal transducer molecules in LPS signaling in human dermal microvessel endothelial cells (HDMEC) and THP-1 monocytic cells. LPS stimulation of HDMEC and THP-1 cells initiated an IL-1 receptor-like NF- Kappa B signaling cascade. In transient cotransfection experiments, dominant negative mutants of the IL-1 signaling pathway, including MyD88, IRAK, IRAK2, and TRAF6 inhibited both IL-1- and LPS-induced NF- Kappa B-luciferase activity. LPS-induced NF- Kappa B activation was not inhibited by a dominant negative mutant of TRAF2 that is involved in TNF signaling. LPS- induced activation of NF- Kappa B-responsive reporter gene was not inhibited by IL-1 receptor antagonist. TLR2 and TLR4 were expressed on the cell surface of HDMEC and THP-1 cells. These findings suggest that a signal transduction molecule in the LPS receptor complex may belong to the IL-1 receptor/toll-like receptor (TLR) super family, and the LPS signaling cascade uses an analogous molecular framework for signaling as IL-1 in mononuclear phagocytes and endothelial cells.