Diesel exhaust particulate-induced activation of Stat3 requires activities of EGFR and Src in airway epithelial cells.
In vivo exposure to diesel exhaust particles (DEP) elicits acute inflammatory responses in the lung characterized by inflammatory cell influx and elevated expression of mediators such as cytokines and chemokines. Signal transducers and activators of transcription (STAT) proteins are a family of cytoplasmic transcription factors that are key transducers of signaling in response to cytokine and growth factor stimulation. One member of the STAT family, Stat3, has been implicated as a regulator of inflammation but has not been studied in regard to DEP exposure. The results of this study show that DEP induces Stat3 phosphorylation as early as 1 h following stimulation and that phosphorylated Stat3 translocates into the nucleus. Inhibition of epidermal growth factor receptor (EGFR) and Src activities by the inhibitors PD-153035 and PP2, respectively, abolished the activation of Stat3 by DEP, suggesting that Stat3 activation by DEP requires EGFR and Src kinase activation. The present study suggests that oxidative stress induced by DEP may play a critical role in activating EGFR signaling, as evidenced by the fact that pretreatment with antioxidant prevented the activation of EGFR and Stat3. These findings demonstrate that DEP inhalation can activate proinflammatory Stat3 signaling in vitro.
Cao
Dongsun
D
Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Tal
Tamara L
TL
Graves
Lee M
LM
Gilmour
Ian
I
Linak
William
W
Reed
William
W
Bromberg
Philip A
PA
Samet
James M
JM
D000328:Adult; D002467:Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D052638:Particulate Matter / Q000633:toxicity*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012137:Respiratory System / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013997:Time Factors; D001335:Vehicle Emissions / Q000633:toxicity*; D019061:src-Family Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D052638:Particulate Matter; D050796:STAT3 Transcription Factor; D001335:Vehicle Emissions; D066246:ErbB Receptors; D019061:src-Family Kinases; D010749:Phosphoprotein Phosphatases