Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation.
Adhesion molecules that tether circulating leukocytes to endothelial cells may also transduce or modulate outside-in signals for cellular activation, providing an initial regulatory point in the inflammatory response. Adhesion of human monocytes to P-selectin, the most rapidly expressed endothelial tethering factor, increased the secretion of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) by the leukocytes when they were stimulated with platelet-activating factor. Increased cytokine secretion was specifically inhibited by G1, an anti-P-selectin mAb that prevents P-selectin from binding to its ligand (P-selectin glycoprotein ligand-1) on myeloid cells. Moreover, tethering by P-selectin specifically enhanced nuclear translocation of nuclear factor-kappa B (NF-kappa B), a transcription factor required for expression of MCP-1, TNF-alpha, and other immediate-early genes. These results demonstrate that P-selectin, through its ligands on monocytes, may locally regulate cytokine secretion in inflamed tissues.
Weyrich
A S
AS
Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah Health Sciences Center, Salt Lake City 84112, USA.
McIntyre
T M
TM
McEver
R P
RP
Prescott
S M
SM
Zimmerman
G A
GA
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D018932:Chemokine CCL2; D002630:Chemotactic Factors / Q000096:biosynthesis*; D016384:Consensus Sequence; D006224:Cricetinae; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation; D017781:Genes, Immediate-Early; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D019007:P-Selectin; D010972:Platelet Activating Factor / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D015398:Signal Transduction; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D002630:Chemotactic Factors; D016207:Cytokines; D016328:NF-kappa B; D019007:P-Selectin; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha