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INVOLVEMENT OF TOLL-LIKE RECEPTOR 4 AND MAPK PATHWAYS IN LPS-INDUCED CD40 EXPRESSION IN MONOCYTIC CELLS
WU, W., N. ALEXIS, P. A. BROMBERG, AND D. PEDEN. INVOLVEMENT OF TOLL-LIKE RECEPTOR 4 AND MAPK PATHWAYS IN LPS-INDUCED CD40 EXPRESSION IN MONOCYTIC CELLS. Presented at American Thoracic Society Annual Meeting, San Diego, CA, May 19 - 24, 2006.
CD40 is a co-stimulatory surface molecule actively expressed on mature dendritic cells (DC). Recent studies suggest that endotoxin (LPS) inhalation induces DC maturation in the airways of healthy volunteers. To characterize the effect of LPS on CD40 expression and underlying mechanisms, a human blood monocytic cell line, THP-1, was employed as the in vitro model. Exposure of THP-1 cells to LPS resulted in a time- and dose-dependent increase in CD40 expression. Pre-incubation of THP-1 cells with Toll-like receptor (TLR-4) neutralizing antibody (HTA125) markedly suppressed LPS-induced CD40 expression, implying that LPS induced CD40 expression mainly through TLR-4 receptor signaling pathway. Immunoblotting using phospho-specific antibodies demonstrated that LPS stimulation induced phosphorylation of mitogen-activated protein kinases (MAPKs) including ERK, p38, and JNK, as well as protein kinase B (Akt) in a time-dependent fashion. Inhibition of ERK, p38, and JNK kinase activities with selective pharmacological inhibitors differentially blocked LPS-induced CD40 expression. However, the inhibitor of phosphatidylinositol 3-kinase (PI3K), the upstream kinase of Akt, failed to block LPS-induced CD40 expression. Incubation of THP-1 cells with HTA125 prior to LPS stimulation inhibited JNK, but not ERK and p38 phosphorylation, which suggested that pathways in addition to the TLR-4/JNK are also involved in LPS-induced CD40 expression. In summary, LPS can activate multiple signaling pathways in monocytic cells, leading to activation of transcription factors, and ultimately increased expression of CD40. This work does not necessarily reflect EPA policy. (This work was supported by US EPA Cooperative Agreement CR#829522 awarded to the CEMALB, UNC).
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
HUMAN STUDIES DIVISION