Lipopolysaccharide induces expression of fibronectin alpha 5 beta 1-integrin receptors in human monocytic cells in a protein kinase C-dependent fashion.
LPS is an outer-membrane glycolipid component of gram-negative bacteria known for its fervent ability to activate monocytic cells and for its potent proinflammatory capabilities. In addition, LPS triggers the release of cytokines and chemokines as well as cell-cell adhesion molecules. We postulate that LPS may also affect the expression of matrix-binding integrin receptors, thereby modulating cell-adhesive functions in monocytic cells. To test this hypothesis, we investigated the effects of LPS on the expression of the integrin alpha(5)beta(1), a fibronectin receptor, in a human monocytic cell line (U937) as well as in isolated human peripheral blood mononuclear cells (PBMCs). We found that LPS increased the expression of alpha(5)beta(1) receptors and enhanced the adherence of U937 cells and PBMCs to fibronectin-coated surfaces; this was blocked by anti-alpha(5)beta(1) antibodies. LPS increased alpha(5)-subunit mRNA accumulation in a dose- and time-dependent manner. The induction by LPS occurred, at least in part, at the level of gene transcription as indicated by experiments using alpha(5) intact and deletion promoter constructs. LPS-induced alpha(5) gene transcription was associated with rapid induction of conventional PKC-alpha protein and activity, was blocked by PKC inhibitors, and was mimicked by lipid A. Finally, we found that an anti-CD14 antibody was able to inhibit the LPS response. Overall, the data suggest that LPS stimulates alpha(5) gene transcription via CD14 and PKC-dependent signals to enhance the expression of functional alpha(5)beta(1) receptors in monocytic cells. This process may help stimulate monocytic cell activation and facilitate their migration into fibronectin-containing tissues during infection.
Roman
Jesse
J
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, and The Atlanta Veterans Affairs Medical Center, Georgia 30322, USA. jroman@emory.edu
Ritzenthaler
Jeffrey D
JD
Boles
Bonnie
B
Lois
Manuel
M
Roser-Page
Susanne
S
D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000502:physiology; D005353:Fibronectins; D006801:Humans; D039081:Integrin alpha5beta1 / Q000097:blood* / Q000235:genetics; D008050:Lipid A / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
D005353:Fibronectins; D039081:Integrin alpha5beta1; D008050:Lipid A; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D018808:Transcription Factor AP-1; D011493:Protein Kinase C