Down-regulation of interleukin-16 in human mast cells HMC-1 by Clostridium difficile toxins A and B.
Toxin A (TcdA) and toxin B (TcdB) are the major virulence factors of Clostridium difficile and are the causative agents for clinical symptoms, such as secretory diarrhoea and pseudomembranous colitis. Mast cells are essentially involved in the toxin-induced colonic inflammatory processes. To study the direct effects of these toxins on the expression of inflammatory genes, a DNA microarray containing evaluated probes of 90 selected inflammatory genes was applied to the immature mast cell line HMC-1. TcdA and TcdB induced up-regulation of only a limited number of genes within the early phase of cell treatment. Interleukin-8 (IL-8), transcription factor c-jun and heme oxygenase-1 messenger RNA (mRNA) increased more than 2-fold. In contrast, IL-16, known as a CD4(+) T-cell chemoattractant factor and the chemokine receptor cKit were down-regulated. Stimulation of HMC-1 cells with IL-8 had no effect on IL-16 mRNA level, indicating that both cytokines were independently affected by the toxins. Regulation of both cytokines, however, depended on glucosylation of Rho GTPases as tested by application of enzyme-deficient TcdA or TcdB. Down-regulation of total and secreted IL-16 protein was checked by enzyme-linked immunosorbent assay. The data implicate that TcdA and TcdB affect lymphocyte migration by modulating release of the chemoattractant factor IL-16 from mast cells. In addition, this is the first report showing that Rho GTPases are involved in the regulation of IL-16 expression.
Institut für Toxikologie, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. gerhard.ralf@mh-hannover.de
Ralf
R
Gerhard
Swenja
S
Queisser
Helma
H
Tatge
Gesa
G
Meyer
Oliver
O
Dittrich-Breiholz
Michael
M
Kracht
Hanping
H
Feng
Ingo
I
Just
D019943:Amino Acid Substitution / Q000502:physiology; D001426:Bacterial Proteins / Q000235:genetics / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000235:genetics / Q000494:pharmacology*; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics*; D004768:Enterotoxins / Q000235:genetics / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D006031:Glycosylation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019410:Interleukin-16 / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D007093:Imidazoles; D019410:Interleukin-16; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D011994:Recombinant Proteins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D051547:Heme Oxygenase-1; D019009:Proto-Oncogene Proteins c-kit; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; D020830:rac1 GTP-Binding Protein; D020743:rhoB GTP-Binding Protein; C093642:SB 203580
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