Co-treatment with interferon-γ and 1-methyl tryptophan ameliorates cardiac fibrosis through cardiac myofibroblasts apoptosis

• Published in: Molecular and cellular biochemistry Vol. 458; no. 1-2; pp. 197 - 205
• Main Authors: Lee, Jun-Won, Oh, Ji Eun, Rhee, Ki-Jong, Yoo, Byung-Su, Eom, Young Woo, Park, Sang Wook, Lee, Ji Hyun, Son, Jung-Woo, Youn, Young Jin, Ahn, Min-Soo, Ahn, Sung-Gyun, Kim, Jang-Young, Lee, Seung-Hwan, Yoon, Junghan
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-08-2019; Springer Nature B.V
• Subjects: Actin; Antiviral agents; Apoptosis; Biochemistry; Biological activity; Biomedical and Life Sciences; Cardiology; Cell cycle; Deoxyribonucleic acid; Depletion; DNA; FasL protein; Fibrosis; Heart; Immunomodulation; Interferon; Interferon regulatory factor; Life Sciences; Medical Biochemistry; Muscles; Myocardial infarction; Oncology; Smooth muscle; Tryptophan; Tryptophan 2,3-dioxygenase; γ-Interferon; Interferon-gamma; Indoleamine 2,3-dioxygenase; Myofibroblast; Apoptosis
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-019-03542-7

Cardiac remodeling characterized by cardiac fibrosis is a pathologic process occurring after acute myocardial infarction. Fibrosis can be ameliorated by interferon-gamma (IFN-γ), which is a soluble cytokine showing various effects such as anti-fibrosis, apoptosis, anti-proliferation, immunomodulation, and anti-viral activities. However, the role of IFN-γ in cardiac myofibroblasts is not well established. Therefore, we investigated the anti-fibrotic effects of IFN-γ in human cardiac myofibroblasts (hCMs) in vitro and whether indoleamine 2,3-dioxygenase (IDO), induced by IFN-γ and resulting in cell cycle arrest, plays an important role in regulating the biological activity of hCMs. After IFN-γ treatment, cell signaling pathways and DNA contents were analyzed to assess the biological activity of IFN-γ in hCMs. In addition, an IDO inhibitor (1-methyl tryptophan; 1-MT) was used to assess whether IDO plays a key role in regulating hCMs. IFN-γ significantly inhibited hCM proliferation, and IFN-γ-induced IDO expression caused cell cycle arrest in G0/G1 through tryptophan depletion. Moreover, IFN-γ treatment gradually suppressed the expression of α-smooth muscle actin. When IDO activity was inhibited by 1-MT, marked apoptosis was observed in hCMs through the induction of interferon regulatory factor, Fas, and Fas ligand. Our results suggest that IFN-γ plays key roles in anti-proliferative and anti-fibrotic activities in hCMs and further induces apoptosis via IDO inhibition. In conclusion, co-treatment with IFN-γ and 1-MT can ameliorate fibrosis in cardiac myofibroblasts through apoptosis.