Diverse regulation of microfilament assembly, production of TNF-alpha, and reactive oxygen intermediates by actin modulating substances and inhibitors of ADP-ribosylation in human monocytes stimulated with LPS.
Lipopolysaccharide (LPS), a potent activator of human monocytes, induced F-actin polymerization in a concentration- and time-dependent manner. To test whether cytoskeletal events participate in the control of the LPS-induced ROI and TNF-alpha production, three natural occurring actin-modulating substances, cytochalasin D (Cyt D), latrunculin B (Lat B), and jasplakinolide (JK), were used. Here we show that treatment of monocytes with Cyt D, Lat B, or JK led to a rearrangement of the actin cytoskeleton, which upon addition of LPS was further modified. Cyt D and Lat B induced generation of ROI in the absence of LPS and enhanced the LPS-triggered respiratory burst. JK also proved to be a potent activator of ROI-production but only in the presence of LPS. TNF-alpha production was hardly affected by the three substances. There was no correlation between a specific state of Cyt D-, Lat B-, or JK-modified actin polymerization and ROI-production. Inhibitors of ADP-ribosylation proved to be activators of F-actin polymerization. They were shown to prevent ROI- and TNF-alpha production and to reduce the capability of LPS to mediate maximal F-actin assembly. At concentrations at which inhibition was greatest, maximal blockage of ROI and TNF-alpha production was observed. These findings may argue for a role of ADP-ribosylation in the transduction pathways mediating the biological responses, with involvement in the assembly of actin-containing cytoskeletal microfilaments.
Rossol
M
M
Institute of Zoology, Department of Immunobiology, University of Leipzig, Leipzig, Germany.
Gärtner
D
D
Hauschildt
S
S
D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D047630:Depsipeptides; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010766:Phosphorylation; D011108:Polymers / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000199:Actins; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047630:Depsipeptides; D008070:Lipopolysaccharides; D019384:Nucleic Acid Synthesis Inhibitors; D010456:Peptides, Cyclic; D011108:Polymers; D017382:Reactive Oxygen Species; D013844:Thiazoles; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha; C057531:jasplakinolide; D000246:Adenosine Diphosphate Ribose; D015638:Cytochalasin D; C037068:latrunculin B