Mechanism Underlying Defective Interferon Gamma-Induced IDO Expression in Non-obese Diabetic Mouse Fibroblasts

Autor: Yunyuan Li, Reza B. Jalili, Azadeh Hosseini-Tabatabaei, Aziz Ghahary, Ruhangiz T. Kilani, Alireza Moeen Rezakhanlou
Rok vydání: 2012
Předmět:
Lipopolysaccharides
Male
lcsh:Medicine
Gene Expression
Genes
MHC Class I
Nod
Mice
Endocrinology
0302 clinical medicine
Mice
Inbred NOD
Transduction
Genetic
Molecular Cell Biology
Membrane Receptor Signaling
Interferon gamma
STAT1
Phosphorylation
lcsh:Science
Skin
NOD mice
0303 health sciences
Multidisciplinary
biology
Tryptophan
Signaling in Selected Disciplines
STAT1 Transcription Factor
medicine.anatomical_structure
030220 oncology & carcinogenesis
Medicine
Female
Collagen
Signal transduction
Immunologic Receptor Signaling
Signal Transduction
Research Article
medicine.drug
medicine.medical_specialty
Immunology
Immunological Signaling
Microbiology
Autoimmune Diseases
Immunomodulation
Interferon-gamma
03 medical and health sciences
Immune system
Internal medicine
medicine
Animals
Indoleamine-Pyrrole 2
3
-Dioxygenase
Fibroblast
Biology
030304 developmental biology
Diabetic Endocrinology
lcsh:R
Immunity
Immunoregulation
Dendritic Cells
Diabetes Mellitus Type 1
Fibroblasts
Mice
Inbred C57BL
Diabetes Mellitus
Type 1
STAT protein
biology.protein
lcsh:Q
Clinical Immunology
Spleen
Zdroj: PLoS ONE
PLoS ONE, Vol 7, Iss 5, p e37747 (2012)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0037747
Popis: Indoleamine 2,3-dioxygenase (IDO) can locally suppress T cell-mediated immune responses. It has been shown that defective self-tolerance in early prediabetic female non-obese diabetic (NOD) mice can be attributed to the impaired interferon-gamma (IFN-γ)- induced IDO expression in dendritic cells of these animals. As IFN-γ can induce IDO in both dendritic cells and fibroblasts, we asked the question of whether there exists a similar defect in IFN-γ-induced IDO expression in NOD mice dermal fibroblasts. To this end, we examined the effect of IFN-γ on expression of IDO and its enzymatic activity in NOD dermal fibroblasts. The results showed that fibroblasts from either prediabetic (8 wks of age) female or male, and diabetic female or male (12 and 24 wks of age respectively) NOD mice failed to express IDO in response to IFN-γ treatment. To find underlying mechanisms, we scrutinized the IFN- γ signaling pathway and investigated expression of other IFN-γ-modulated factors including major histocompatibility complex class I (MHC-I) and type I collagen (COL-I). The findings revealed a defect of signal transducer and activator of transcription 1 (STAT1) phosphorylation in NOD cells relative to that of controls. Furthermore, we found an increase in MHC-I and suppression of COL-I expression in fibroblasts from both NOD and control mice following IFN-γ treatment; indicating that the impaired response to IFN-γ in NOD fibroblasts is specific to IDO gene. Finally, we showed that an IFN-γ-independent IDO expression pathway i.e. lipopolysaccharide (LPS)-mediated-c-Jun kinase is operative in NOD mice fibroblast. In conclusion, the findings of this study for the first time indicate that IFN-γ fails to induce IDO expression in NOD dermal fibroblasts; this may partially be due to defective STAT1 phosphorylation in IFN-γ-induced-IDO signaling pathway.
Databáze: OpenAIRE
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