Silica nanoparticles induce cytokine responses in lung epithelial cells through activation of a p38/TACE/TGF-α/EGFR-pathway and NF-κΒ signalling.
Amorphous silica nanoparticles (SiNPs) have previously been shown to induce marked cytokine (interleukin-6; IL-6 and interleukin-8; CXCL8/IL-8) responses independently of particle uptake in human bronchial epithelial BEAS-2B cells. In this study the involvement of the mitogen-activated protein kinases (MAP-kinases), nuclear factor-kappa Β (NF-κΒ) and in particular tumour necrosis factor-α converting enzyme (TACE) and-epidermal growth factor receptor (EGFR) signalling pathways were examined in triggering of IL-6 and CXCL8 release after exposure to a 50nm silica nanoparticle (Si50). Exposure to Si50 increased phosphorylation of NF-κΒ p65 and MAP-kinases p38 and JUN-N-terminal protein kinase pathways (JNK), but not extracellular signal regulated kinases (ERK). Inhibition of NF-κΒ and p38 reduced the cytokine responses to Si50, whereas neither JNK- nor ERK-inhibition exerted any significant effect on the responses to Si50. Increases in membrane-bound transforming growth factor-α (TGF-α) release and EGFR phosphorylation were also observed after Si50 exposure, and pre-treatment with inhibitors of these pathways reduced the release of IL-6 and CXCL8, but did not affect the Si50-induced phosphorylation of p38 and p65. In contrast, p38-inhibition partially reduced Si50-induced TGF-α release, while the p65-inhibition was without effect. Overall, our results indicate that Si50-induced IL-6 and CXCL8 responses in BEAS-2B cells were regulated through combined activation of several pathways, including NF-κΒ and p38/TACE/TGF-α/EGFR signalling. The study identifies critical, initial events in the triggering of pro-inflammatory responses by nanoparticles.
Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway. Electronic address: tonje.skuland@fhi.no.
Tonje
T
Skuland
Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway.
Johan
J
Ovrevik
Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway.
Marit
M
Låg
Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway.
Per
P
Schwarze
Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway.
Magne
M
Refsnes
D051722:ADAM Proteins / Q000502:physiology*; D000072198:ADAM17 Protein; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000378:metabolism*; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D015848:Interleukin-5 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology*; D053758:Nanoparticles / Q000633:toxicity*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000633:toxicity*; D051996:Transcription Factor RelA / Q000096:biosynthesis / Q000235:genetics; D016211:Transforming Growth Factor alpha / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D016207:Cytokines; D015848:Interleukin-5; D016209:Interleukin-8; D016328:NF-kappa B; D051996:Transcription Factor RelA; D016211:Transforming Growth Factor alpha; D012822:Silicon Dioxide; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
BEAS-2B; Cytokines; Intracellular signalling; Particles