Chromium(VI) stimulates Fyn to initiate innate immune gene induction in human airway epithelial cells.
Mechanisms for pathogenic metal signaling in airway injury or disease promotion are poorly understood. It is widely believed that one mechanism for pathogenic and possible carcinogenic effects of inhaled chromium (Cr(VI)) is inhibition of inducible gene transactivation. However, we recently reported that Cr(VI) inhibition of Sp1-dependent transactivation required signal transducer and activator of transcription 1 (STAT1)-dependent expression of an inhibitory protein in airway epithelium. Thus, Cr(VI) exposures can induce genes, and we hypothesized that this induction resulted from Cr(VI) signaling through an innate immune-like STAT1-dependent pathway initiated by Fyn. Exposure of human airway epithelial (BEAS-2B) cells to Cr(VI) selectively transactivated the STAT-responsive interferon-stimulated response element (ISRE) and induced ISRE-driven transactivation of interferon regulatory factor 7 (IRF7), without affecting the gamma interferon-activated site (GAS)-driven IRF1 expression. Cr(VI)-induced IRF7 was absent or greatly reduced in cells that lacked STAT1, were treated with the Src family kinase inhibitor, PP2, or lacked Fyn. Expressing Fyn, but not Src, in mouse embryonic fibroblasts cells null for Src, Yes, and Fyn restored Cr(VI)-stimulated STAT1 tyrosine phosphorylation and IRF7 expression. Finally, shRNA knockdown of Fyn in BEAS-2B cells prevented Cr(VI)-activated STAT1 transactivation of IRF7. These data support a novel mechanism through which Cr(VI) stimulates Fyn to initiate interferon-like signaling for STAT1-dependent gene transactivation.
Nemec
Antonia A
AA
University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania 15219, USA.
Zubritsky
Lindsey M
LM
Barchowsky
Aaron
A
D000818:Animals; D002274:Carcinogens, Environmental / Q000633:toxicity; D002857:Chromium / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D050839:Interferon Regulatory Factor-7 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism* / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction
D002274:Carcinogens, Environmental; D050839:Interferon Regulatory Factor-7; D002857:Chromium; C074702:chromium hexavalent ion; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn