title: Regulation by rho family GTPases of IL-1 receptor induced signaling: C3-like chimeric toxin and Clostridium difficile toxin B inhibit signaling pathways involved in IL-2 gene expression.
abstract: In this study the participation of Rho family GTPases in the regulation of IL-1-activated protein kinase cascades controlling IL-2 synthesis was investigated in murine EL-4 thymoma cells. The recombinant C3-like chimeric toxin, which consists of the C3 toxin of Clostridium limosum and the N-terminal part of Clostridium botulinum C2 toxin (C2IN-C3) interacting with the C2II binding subunit to facilitate uptake into cells, and selectively inactivates Rho A by ADP-ribosylation, prevented IL-1-stimulated activation of Jun-NH2-terminal-kinases (JNK) and p38 mitogen-activated-protein kinases (MAPK). UDP-monoglucosylation and concomitant inactivation of Rho A and of Rac-2 by Clostridium difficile toxin B also inhibited IL-1-induced activation of JNK and p38 MAPK, but additionally inhibited activation of the extracellular-regulated-kinase pathway and DNA binding of the transcription factor NFkappaB. Accordingly, pre-treatment of cells with C21N-C3 fusion toxin only decreased IL-1-stimulated IL-2 synthesis by 50%, while in C. difficile toxin B-treated cells IL-1-induced IL-2 secretion was reduced by 90%. These results imply that together with Rho A an additional member of the Rho family G proteins, i.e. Rac-2, is critically involved as an upstream regulator in IL-1-induced activation of different MAPK, stress-activated protein kinases, and in NFkappaB activation controlling IL-2 gene expression in response to IL-1, acting in close proximity to the IL-1-receptor complex.
authors.affiliation: Institute of Pharmacology, Medical School Hannover, Hannover, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Dreikhausen
authors.forename: G
authors.initials: G
authors.lastname: Varga
authors.forename: F
authors.initials: F
authors.lastname: Hofmann
authors.forename: H
authors.initials: H
authors.lastname: Barth
authors.forename: K
authors.initials: K
authors.lastname: Aktories
authors.forename: K
authors.initials: K
authors.lastname: Resch
authors.forename: M
authors.initials: M
authors.lastname: Szamel
mesh_terms: D000818:Animals; D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000494:pharmacology*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004247:DNA; D007375:Interleukin-1; D007376:Interleukin-2; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C031815:toxB protein, Clostridium difficile