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The role of NF-kappaB, IRF-1, and STAT-1alpha transcription factors in the iNOS gene induction by gliadin and IFN-gamma in RAW 264.7 macrophages.
- Source :
-
Journal of molecular medicine (Berlin, Germany) [J Mol Med (Berl)] 2006 Jan; Vol. 84 (1), pp. 65-74. Date of Electronic Publication: 2005 Nov 12. - Publication Year :
- 2006
-
Abstract
- Nitric oxide (NO) plays an important role in the pathogenesis of celiac disease. We have examined the involvement of nuclear factor-kappaB (NF-kappaB), interferon regulatory factor-1 (IRF-1), and signal transducer and activator of transcription-1alpha (STAT-1alpha) on the synergistic induction of inducible nitric oxide synthase (iNOS) gene expression by gliadin (G) in association with interferon-gamma (IFN-gamma) in RAW 264.7 macrophages. We found that IFN-gamma was efficient in enhancing the basal transcription of the iNOS promoter at 1, 6, and 24 h, whereas G had no effect. The G plus IFN-gamma association caused an increase in iNOS promoter activity which was inhibited by pyrrolidine dithiocarbammate (PDTC) at 6 and 24 h as well as by genistein (Gen) and tyrphostine B42 (TB42) at 1 h, inhibitors of NF-kappaB, IRF-1, and STAT-1alpha activation, respectively. Similarly, the IFN-gamma and G combination treatment led to a higher increase in iNOS mRNA levels at 1, 6, and 24 h compared with IFN-gamma alone. Gen and TB42 inhibited iNOS mRNA levels at 1 h, whereas PDTC inhibited iNOS mRNA levels at 6 and 24 h. In addition, the synergistic induction of iNOS gene expression by G plus IFN-gamma correlated with the induction of NF-kappaB, IRF-1, and STAT-1alpha/DNA binding activity and mRNA expression. In conclusion, our study, which provides evidence that the effect of G on iNOS gene transcription in IFN-gamma-stimulated RAW 264.7 cells can be ascribed to all three transcription factors, may contribute to lead to new insights into the molecular mechanisms governing the inflammatory process in celiac disease.
- Subjects :
- Animals
Antioxidants pharmacology
Celiac Disease metabolism
Cell Line
Enzyme Inhibitors pharmacology
Gene Expression Regulation, Enzymologic drug effects
Genistein pharmacology
Humans
Macrophages cytology
Macrophages drug effects
Mice
NF-kappa B antagonists & inhibitors
Nitric Oxide Synthase Type II genetics
Nitrites metabolism
Protein Isoforms genetics
Protein Isoforms metabolism
Pyrrolidines pharmacology
STAT1 Transcription Factor genetics
Thiocarbamates pharmacology
Transcriptional Activation
Tyrphostins pharmacology
Gliadin metabolism
Interferon Regulatory Factor-1 metabolism
Interferon-gamma metabolism
Macrophages physiology
NF-kappa B metabolism
Nitric Oxide Synthase Type II metabolism
STAT1 Transcription Factor metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0946-2716
- Volume :
- 84
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of molecular medicine (Berlin, Germany)
- Publication Type :
- Academic Journal
- Accession number :
- 16284791
- Full Text :
- https://doi.org/10.1007/s00109-005-0713-x