Ultrafine carbon particles induce apoptosis and proliferation in rat lung epithelial cells via specific signaling pathways both using EGF-R

Abstract

Apoptosis and proliferation are important causes of adverse health effects induced by inhaled ultrafine particles. The molecular mechanisms of particle cell interactions mediating these end points are therefore a major topic of current particle toxicology and molecular preventive medicine. Initial studies revealed that ultrafine particles induce apoptosis and proliferation in parallel in rat lung epithelial cells, dependent on time and dosage. With these end points, two antagonistic reactions seem to be induced by the same extracellular stimulus. It was therefore investigated whether proliferation is induced directly by the particles or as a compensation of particle-caused cell death. Experimental conditions excluding compensatory proliferation demonstrated that both end points are induced independently by specific signaling pathways. Events eliciting signaling cascades leading to apoptosis and proliferation were studied with specific inhibitors of membrane receptors. Epidermal growth factor receptor (EGF-R) kinase activity was identified as essential for apoptosis as well as for proliferation. As ultrafine particle-induced proliferation alone was dependent on the activation of beta1-integrins, these membrane receptors are suggested to mediate the specificity of EGF-R signaling concerning the decision as to whether apoptosis or proliferation is triggered. Accordingly, MAP kinase signaling downstream of EGF-R showed comparable specificity with regard to receptor-dependent induction of apoptosis and proliferation. As key mediators of signaling cascades, the activation of extracellular signal-regulated kinases 1 and 2 proved to be specific for proliferation in a beta1-integrin-dependent manner, whereas phosphorylation of c-Jun NH2-terminal kinases 1 and 2 was correlated with the induction of apoptosis.

Carbon nanoparticle-induced lung epithelial cell proliferation is mediated by receptor-dependent Akt activation

“…The elevated background after 16 h has been described earlier (5) as induced by the starving conditions under which the cells have to be kept to identify treatmentspecific reactions. Interestingly, this time course in phosphorylation has striking similarities to the time course in ERK1/2 activation that we described in our previous studies (28).…”

“…Nanoparticles have been shown to act as an extracellular stimulus that induces signaling dependent on the membrane receptors EGF-R and ␤ 1 -integrin (28). Because Akt activation was known to be initiated by these receptors on cell attachment, we investigated whether this signaling cascade is also triggered by nanoparticles.…”

“…Previously, we (28) observed that treatment with two types of nanoparticles, carbon particles [nanoparticulate carbon black, (NPCB; Printex 90)] as well as silica particles (amorphous SiO 2 ), both with a median diameter of 14 nm, induced proliferation in a rat lung epithelial cell line. Investigating signaling events relevant for this specific outcome, we were able to demonstrate that the membrane receptors epidermal growth factor receptor (EGF-R) and ␤ 1 -integrin are involved in particle-induced activation of the MAPKs ERK1/2 in response to nanoparticle treatment.…”

Big Signals from Small Particles: Regulation of Cell Signaling Pathways by Nanoparticles

“…31 In an earlier study, Sydlik et al could show that ultrafine carbon particles activate EGFR in lung epithelial cells subsequently leading in parallel to apoptotic events as well as proliferation. 63 While the kinase activity of EGFR was found essential for both processes, β1-integrin-mediated activation of ERK was instrumental for proliferation, whereas apoptosis was mediated by activation of cJun. In other studies, it was demonstrated, that in human bronchial epithelial cells, exposure to PM2.5 particles (i.e.…”

“…So far, NP toxicity was mainly described through the induction of oxidative stress, inflammation and apoptosis as cellular responses. 18 Cell death highly depends on NP concentration, duration of the exposure and the cellular system investigated and both, programmed cell death (apoptosis) as well as necrosis, were observed as an outcome 63,71 . However, ROS also play important roles as intercellular second messengers and activators of specific pathways.…”