Endotoxin suppresses matrix protein-induced upregulation of PMN candicidal activity: an effect reversed by low-dose TNF-alpha.
We investigated the relationship of polymorphonuclear leukocyte (PMN) candicidal activity, matrix proteins, and lipopolysaccharide (LPS) to determine how LPS modulates the normal enhancing effect of matrix proteins on PMN candicidal activity. LPS reduced PMN candicidal activity when PMN were adhered in the presence of either fibronectin or laminin. In the presence of fibronectin or laminin, LPS reduced CD11b/CD18 expression (the fibronectin receptor) as assessed using sheep erythrocytes coated with C3bi. Experiments with 125I-fibronectin and 125I-RGDS (Arg-Gly-Asp-Ser) demonstrated that LPS reduced both the binding of fibronectin and the bioavailability of the binding epitope on the PMN surface. Stimulating the PMN oxidative burst with PMA but not FMLP also reduced fibronectin and RGDS binding. Incubation of LPS-treated PMN with staurosporine blocked the decrease in fibronectin and RGDS binding. Exposure of PMN to LPS plus low-dose TNF-alpha restored both fibronectin and RGDS binding with a concomitant increase in CD11b/CD18 surface expression. Low-dose TNF-alpha restored PMN candicidal activity in the presence of LPS and was most effective if PMN were preadhered to fibronectin. These results demonstrate that: (1) matrix proteins enhance normal PMN candicidal activity, (2) LPS reduces PMN candicidal activity in the presence of matrix proteins, (3) stimulation of the PMN oxidative burst in particular via protein kinase c activation reduces the bioavailability of the fibronectin receptor, and (4) low-dose TNF-alpha may restore PMN candicidal activity in part by upregulating the surface receptor for fibronectin binding.
Simms
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Division of Surgical Research, Rhode Island Hospital/Brown University School of Medicine, Providence 02903.
D'Amico
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D002176:Candida albicans; D002448:Cell Adhesion; D004731:Endotoxins / Q000494:pharmacology*; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
D004731:Endotoxins; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D008070:Lipopolysaccharides; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; C046617:arginyl-glycyl-aspartyl-serine; D011493:Protein Kinase C