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Published ahead of print on December 18, 2008, doi:10.1165/rcmb.2008-0146OC

Am. J. Respir. Cell Mol. Biol., Volume 41, Number 1, July 2009, 114-123

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Submitted on April 11, 2008
Accepted on December 11, 2008

Alterations in Gene Expression in Human Mesothelial Cells Correlate with Mineral Pathogenicity

Arti Shukla1*, Maximilian B MacPherson1, Jedd Hillegass1, Maria E Ramos-Nino1, Vlada Alexeeva1, Pamela M Vacek2, Jeffrey P Bond3, Harvey I. Pass4, Chad Steele5, and Brooke T Mossman1

1 Department of Pathology, University of Vermont College of Medicine, Burlington, United States, 2 Department of Medical Biostatistics, University of Vermont College of Medicine, Burlington, United States, 3 Department of Microbiology and Molecular Genetics, University of Vermont College of Medicine, Burlington, United States, 4 Department of Cardiothoracic Surgery, NYU Langone Medical Center, New York, New York, United States, 5 Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States

* To whom correspondence should be addressed. E-mail: arti.shukla{at}uvm.edu.

Human mesothelial cells (LP9/TERT-1) were exposed to low and high (15 and 75 µm2/cm2 dish) equal surface area concentrations of crocidolite asbestos, nonfibrous talc, fine titanium dioxide (TiO2), or glass beads for 8 or 24 h. RNA was then isolated for Affymetrix microarrays, GeneSifter analysis and QRT-PCR. Gene changes by asbestos were concentration- and time-dependent. At low nontoxic concentrations, asbestos caused significant changes in mRNA expression of 29 genes at 8 h and 205 genes at 24 h, whereas changes in mRNA levels of 236 genes occurred in cells exposed to high concentrations of asbestos for 8 h. Human primary pleural mesothelial cells also showed the same patterns of increased gene expression by asbestos. Nonfibrous talc at low concentrations in LP9/TERT-1 mesothelial cells caused increased expression of 1 gene Activating Transcription Factor 3 (ATF3) at 8 h and no changes at 24 h, whereas expression levels of 30 genes were elevated at 8 h at high talc concentrations. Fine TiO2 or glass beads caused no changes in gene expression. In human ovarian epithelial (IOSE) cells, asbestos at high concentrations elevated expression of 2 genes (NR4A2, MIP2) at 8 h and 16 genes at 24 h that were distinct from those elevated in mesothelial cells. Since ATF3 was the most highly expressed gene by asbestos, its functional importance in cytokine production by LP9/TERT-1 cells was assessed using siRNA approaches. Results reveal that ATF3 modulates production of inflammatory cytokines (IL-1{beta}, IL-13, G-CSF) and growth factors (VEGF and PDGF-BB) in human mesothelial cells.
Key words: Mesothelioma • Crocidolite asbestos • Talc • Titanium dioxide • Gene profiling






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