ERK5 protein promotes, whereas MEK1 protein differentially regulates, the Toll-like receptor 2 protein-dependent activation of human endothelial cells and monocytes.
Endothelial cell (EC) Toll-like receptor 2 (TLR2) activation up-regulates the expression of inflammatory mediators and of TLR2 itself and modulates important endothelial functions, including coagulation and permeability. We defined TLR2 signaling pathways in EC and tested the hypothesis that TLR2 signaling differs in EC and monocytes. We found that ERK5, heretofore unrecognized as mediating TLR2 activation in any cell type, is a central mediator of TLR2-dependent inflammatory signaling in human umbilical vein endothelial cells, primary human lung microvascular EC, and human monocytes. Additionally, we observed that, although MEK1 negatively regulates TLR2 signaling in EC, MEK1 promotes TLR2 signaling in monocytes. We also noted that activation of TLR2 led to the up-regulation of intracellularly expressed TLR2 and inflammatory mediators via NF-κB, JNK, and p38-MAPK. Finally, we found that p38-MAPK, JNK, ERK5, and NF-κB promote the attachment of human neutrophils to lung microvascular EC that were pretreated with TLR2 agonists. This study newly identifies ERK5 as a key regulator of TLR2 signaling in EC and monocytes and indicates that there are fundamental differences in TLR signaling pathways between EC and monocytes.
Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143,USA. wilhelmsenk@anesthesia.ucsf.edu
Kevin
K
Wilhelmsen
Kailin R
KR
Mesa
Jennifer
J
Lucero
Fengyun
F
Xu
Judith
J
Hellman
D002448:Cell Adhesion; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000502:physiology*; D048054:Mitogen-Activated Protein Kinase 7 / Q000502:physiology*; D009000:Monocytes / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
D016328:NF-kappa B; D034741:RNA, Small Interfering; D051195:Toll-Like Receptor 2; D048054:Mitogen-Activated Protein Kinase 7; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human