Activation of MAPKs in human bronchial epithelial cells exposed to metals

Abstract

We have previously shown that in vitro exposure to metallic compounds enhances expression of interleukin (IL)-6, IL-8, and tumor necrosis factor-α in human bronchial epithelial cells. To characterize signaling pathways involved in metal-induced expression of inflammatory mediators and to identify metals that activate them, we studied the effects of As, Cr, Cu, Fe, Ni, V, and Zn on the mitogen-activated protein kinases (MAPK) extracellular receptor kinase (ERK), c-Jun NH2-terminal kinase (JNK), and P38 in BEAS cells. Noncytotoxic concentrations of As, V, and Zn induced a rapid phosphorylation of MAPK in BEAS cells. Activity assays confirmed marked activation of ERK, JNK, and P38 in BEAS cells exposed to As, V, and Zn. Cr and Cu exposure resulted in a relatively small activation of MAPK, whereas Fe and Ni did not activate MAPK under these conditions. Similarly, the transcription factors c-Jun and ATF-2, substrates of JNK and P38, respectively, were markedly phosphorylated in BEAS cells treated with As, Cr, Cu, V, and Zn. The same acute exposure to As, V, or Zn that activated MAPK was sufficient to induce a subsequent increase in IL-8 protein expression in BEAS cells. These data suggest that MAPK may mediate metal-induced expression of inflammatory proteins in human bronchial epithelial cells.

p38 Activation Is Required Upstream of Potassium Current Enhancement and Caspase Cleavage in Thiol Oxidant-Induced Neuronal Apoptosis

“…We also find evidence that the intracellular signaling cascades activated by DTDP appear to be similar to those observed by other researchers after exposure to extracellular zinc. Samet et al (1998) reported p38 and ERK activation in human bronchial cells after zinc exposure. Although we observed increases in both ERK and p38 after DTDP treatment, only p38 activation contributes significantly to the observed neurotoxicity.…”

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

“…MKP5 has been shown to be able to deactivate all MAPK members, with some selectivity for the JNK/SAPK members [63,64]. Cr-induced activation of ERK, JNK and p38 pathways has been shown in a number of different cell lines, while the activation pattern is dependent on the dose/duration of the exposure [57,[65][66][67]. It has been suggested that Cr(VI) can potentially activate inhibitory MKPs [66].…”

Phosphoproteomic profiling of arsenite-treated human small airway epithelial cells

“…Mutations in Flt3, including internal tandem duplication, occur in the juxtamembrane domain at which arsenite trioxide is the most potent signal transducer (40,41). Flt3 internal tandem duplication is a prevalent mutation in various signaling pathways including the MAPK/extracellular signal-regulated kinase (ERK) pathway (18). However, to the best of our knowledge, the role of Flt3 in phospho-receptor tyrosine kinase pathway has not been documented in other systems.…”

“…It has been shown that arsenite can induce reactive oxygen species production and cause DNA damage (13)(14)(15)(16). It may also interfere with the DNA repair system or DNA methylation state, induce inhibition of p53, increase cell proliferation, and alter signal transduction pathways that lead to the activation of transcription factors (17)(18)(19)(20). However, knowledge on the exact carcinogenic mechanism and valid model systems for this compound is still lacking, which creates even more concern for adverse potential of this important environmental pollutant (21).…”