Deoxynivalenol induces ectodomain shedding of TNF receptor 1 and thereby inhibits the TNF-α-induced NF-κB signaling pathway.
Trichothecene mycotoxins are known to inhibit eukaryotic translation and to trigger the ribotoxic stress response, which regulates gene expression via the activation of the mitogen-activated protein (MAP) kinase superfamily. In this study, we found that deoxynivalenol induced the ectodomain shedding of tumor necrosis factor (TNF) receptor 1 (TNFRSF1A) and thereby inhibited the TNF-α-induced signaling pathway. In human lung carcinoma A549 cells, deoxynivalenol and 3-acetyldeoxynivalenol inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) induced by TNF-α more strongly than that induced by interleukin 1α (IL-1α), whereas T-2 toxin and verrucarin A exerted nonselective inhibitory effects. Deoxynivalenol and 3-acetyldeoxynivalenol also inhibited the nuclear factor κB (NF-κB) signaling pathway induced by TNF-α, but not that induced by IL-1α. Consistent with these findings, deoxynivalenol and 3-acetyldeoxynivalenol induced the ectodomain shedding of TNF receptor 1 by TNF-α-converting enzyme (TACE), also known as a disintegrin and metalloproteinase 17 (ADAM17). In addition to the TACE inhibitor TAPI-2, the MAP kinase or extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126 and the p38 MAP kinase inhibitor SB203580, but not the c-Jun N-terminal kinase (JNK) inhibitor SP600125, suppressed the ectodomain shedding of TNF receptor 1 induced by deoxynivalenol and reversed its selective inhibition of TNF-α-induced ICAM-1 expression. Our results demonstrate that deoxynivalenol induces the TACE-dependent ectodomain shedding of TNF receptor 1 via the activation of ERK and p38 MAP kinase, and thereby inhibits the TNF-α-induced NF-κB signaling pathway.
Department of Applied Biology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto, Japan.
Seiya
S
Hirano
Takao
T
Kataoka
D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053582:Interleukin-1alpha / Q000494:pharmacology; D009183:Mycotoxins / Q000633:toxicity; D016328:NF-kappa B / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014255:Trichothecenes / Q000494:pharmacology* / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D053582:Interleukin-1alpha; D009183:Mycotoxins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D014255:Trichothecenes; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C043247:3-acetyldeoxynivalenol; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C007262:deoxynivalenol