Molecular events in human T cells treated with diesel exhaust particles or formaldehyde that underlie their diminished interferon-gamma and interleukin-10 production.
BACKGROUND
A series of epidemiological and experimental studies have suggested that diesel exhaust particles (DEP) and formaldehyde (FA) may help trigger T helper type 2 (Th2)-mediated allergic responses.


METHODS
To identify the molecular events by which DEP and FA induce a Th2-skewed immune response, we stimulated T cells from healthy subjects with anti-CD3/anti-CD28 monoclonal antibodies and examined the effect of pretreatment with DEP or FA on mitogen-activated protein kinases (MAPKs) and nuclear factor (NF)-kappaB by Western blotting and colorimetric NF-kappaB assays. We also examined the mRNA expression profiles of the T cells by microarray and real-time PCR analyses.


RESULTS
FA selectively suppressed interferon (IFN)-gamma and interleukin-10 mRNA expression and protein production in stimulated T cells, as we previously reported with DEP. In the present study, we found that both DEP and FA suppressed NF-kappaB signaling and activated MAPKs. Both also significantly suppressed the mRNA expression of T-bet, Txk and c-Maf. Microarrays revealed significant augmentation of the expression of 2 FoxO3a-dependent genes, namely glucocorticoid-induced leucine zipper and growth arrest and DNA damage-inducible gene 45 alpha (Gadd45a), which are known to modulate T cell immune responses. Treatment with N-acetylcysteine reversed the augmented Gadd45a mRNA response and caused the suppressed IFN-gamma mRNA response to recover.


CONCLUSIONS
DEP and FA have similar transcriptional and nontranscriptional effects on T cell signaling that together promote a Th2-skewed immune response.
Sasaki
Yoshinori
Y
Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Ohtani
Tomoyuki
T
Ito
Yumiko
Y
Mizuashi
Masato
M
Nakagawa
Satoshi
S
Furukawa
Toru
T
Horii
Akira
A
Aiba
Setsuya
S
D000328:Adult; D000393:Air Pollutants / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics; D056970:Co-Repressor Proteins; D005557:Formaldehyde / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D051218:Lymphocyte Antigen 96 / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D052638:Particulate Matter / Q000494:pharmacology; D056950:Period Circadian Proteins; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D001335:Vehicle Emissions; D055815:Young Adult; D000098815:T-bet Transcription Factor; D000097642:GADD45 Proteins
D000393:Air Pollutants; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D005557:Formaldehyde; D020672:I-kappa B Proteins; D007371:Interferon-gamma; D016753:Interleukin-10; D051218:Lymphocyte Antigen 96; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D052638:Particulate Matter; D056950:Period Circadian Proteins; D011505:Protein-Tyrosine Kinases; D051257:Proto-Oncogene Proteins c-maf; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D001335:Vehicle Emissions; D000098815:T-bet Transcription Factor; C492192:ATRN protein, human; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C495377:LY96 protein, human; C495607:MAF protein, human; C413449:PBXIP1 protein, human; C539022:PER1 protein, human; C404226:TSC22D3 protein, human; C089848:Tec protein-tyrosine kinase