ZHANG FX, FAURE E, ARDITI M; Interscience Conference on Antimicrobial Agents and Chemotherapy.
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1999 Sep 26-29; 39: 382 (abstract no. 1592).
Cedars-Sinai Med. Ctr., Div. of Pediatric Infectious Diseases, UCLA Sch. of Med., Los Angeles, CA.
LPS-mediated immune responses, including activation of monocytes, macrophages, and endothelial cells (EC) play an important role in the pathogenesis of gram-negative sepsis and septic shock. We have previously shown that LPS stimulates phosphorylation and activation of several MAP kinases, including p38 MAPK, and induces NF-k B activation and IL-6 synthesis in EC. Recent studies have identified Toll-like receptors (TLRs) as a potential class of LPS receptors. We have recently shown that LPS shares the IL-1 receptor signaling molecules to activate NF-k B, most likely using TLRs, in endothelial cells and THP-1 cells (Zhang et al., JBC 1999: 274:7611). However, the exact role of p38 MAP kinase in IL-6 synthesis and the connection between p38 MAPK pathway with the NFk B activation remain unclear. In this study, HDMEC were transiently co-transfected (Fugen 6) with a dominant negative construct of p38 MAPK (DN p38; p38 TY * AF), reporter-promoter-luciferase constructs of either human IL-6 or NF-k B, and beta-gal contsruct. Cells were lysed and luciferase and beta-gal activities were measured to normalize for transfection efficiency. In triplicate experiments, overexpression of DNp38 construct inhibited (mean inhibition of 90%) both LPS-induced human IL-6 promoter, and NF-k B- luciferase activities. Treatment of HDMEC with the p38 MAP kinase inhibitor (SB203580) also decreased (mean inhibition of 50%) IL-6 promoter and NF-k B-luciferase activity. Taken together, our data suggest that p38 MAPK is required for LPS-induced IL-6 synthesis in endothelial cells. Furthermore, our findings suggest that the p38 MAPK pathway may be involved in LPS-induced transactivation of NF-k B in EC. Further work dissecting signaling events proximal and distal to p38 MAP kinase is under way in our laboratory.
Publication Types:
Keywords:
- Animals
- Endothelial Cells
- Humans
- Imidazoles
- Interleukin-6
- Lipopolysaccharides
- Mitogen-Activated Protein Kinase 14
- Mitogen-Activated Protein Kinases
- Monocytes
- Pyridines
- SB 203580
- Signal Transduction
- Trans-Activation (Genetics)
- genetics
- immunology
- p38 Mitogen-Activated Protein Kinases
Other ID:
UI: 102245437
From Meeting Abstracts