Differential role of protein kinase C in cytokine induced lymphocyte-endothelium interaction in vitro.
In the present study we investigated the influence of the PKC-inhibitor GF109203X on cytokine- and endotoxin-induced expression of intercellular adhesion molecule 1 (ICAM-1) and on the adhesion of lymphocytes to cytokine-activated endothelial cells. We found that tumour necrosis factor alpha (TNF-alpha)- and lipopolysaccharide (LPS)-induced ICAM-1 expression on a human endothelium-derived cell line (EA.hy926) were unaffected by the PKC-inhibitor and thus appeared to be independent of PKC activation. In contrast, GF109203X significantly reduced ICAM-1 expression induced by interferon-gamma (IFN-gamma) and interleukin-1 (IL-1). The functional relevance of these findings was evaluated in an adhesion assay using human umbilical vein endothelial cells (HUVEC) and peripheral blood mononuclear cells (PBMC). In fact, the IFN-gamma- and IL-1-induced adhesion of PBMC to cytokine treated HUVEC could be down-regulated by the PKC-inhibitor, whereas TNF alpha- and LPS-mediated adhesion was not affected. Additionally, the IL-1-driven ICAM-1 expression on HUVEC as well as the IL-1 induced adhesion of PBMC to HUVEC was found to be TNF-dependent, as both effects could be inhibited by an anti-TNF-alpha monoclonal antibody (MoAb) (MAK195). Based on these data on differential regulation of cytokine-induced lymphocyte-endothelium interactions our study supports the use of PKC-inhibitors as additive modulators in cytokine related pathophysiological conditions.
Eissner
G
G
GSF-Institut für Klinische Molekularbiologie, München, Germany.
Kölch
W
W
Mischak
H
H
Bornkamm
G W
GW
Holler
E
E
D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007371:Interferon-gamma / Q000502:physiology; D007375:Interleukin-1 / Q000502:physiology; D008070:Lipopolysaccharides / Q000276:immunology; D008214:Lymphocytes / Q000502:physiology*; D008301:Maleimides / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D016207:Cytokines; D007211:Indoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D008301:Maleimides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D011493:Protein Kinase C; C070515:bisindolylmaleimide I