PMID- 31006829 OWN - NLM STAT- MEDLINE DCOM- 20190718 LR - 20200225 IS - 1573-4919 (Electronic) IS - 0300-8177 (Print) IS - 0300-8177 (Linking) VI - 458 IP - 1-2 DP - 2019 Aug TI - Co-treatment with interferon-gamma and 1-methyl tryptophan ameliorates cardiac fibrosis through cardiac myofibroblasts apoptosis. PG - 197-205 LID - 10.1007/s11010-019-03542-7 [doi] AB - Cardiac remodeling characterized by cardiac fibrosis is a pathologic process occurring after acute myocardial infarction. Fibrosis can be ameliorated by interferon-gamma (IFN-gamma), 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-gamma in cardiac myofibroblasts is not well established. Therefore, we investigated the anti-fibrotic effects of IFN-gamma in human cardiac myofibroblasts (hCMs) in vitro and whether indoleamine 2,3-dioxygenase (IDO), induced by IFN-gamma and resulting in cell cycle arrest, plays an important role in regulating the biological activity of hCMs. After IFN-gamma treatment, cell signaling pathways and DNA contents were analyzed to assess the biological activity of IFN-gamma 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-gamma significantly inhibited hCM proliferation, and IFN-gamma-induced IDO expression caused cell cycle arrest in G0/G1 through tryptophan depletion. Moreover, IFN-gamma treatment gradually suppressed the expression of alpha-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-gamma 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-gamma and 1-MT can ameliorate fibrosis in cardiac myofibroblasts through apoptosis. FAU - Lee, Jun-Won AU - Lee JW AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Oh, Ji Eun AU - Oh JE AD - Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Rhee, Ki-Jong AU - Rhee KJ AD - Cell Department of Biomedical Laboratory Science, Yonsei University College of Health Sciences, Wonju, Korea. FAU - Yoo, Byung-Su AU - Yoo BS AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. yubs@yonsei.ac.kr. FAU - Eom, Young Woo AU - Eom YW AUID- ORCID: 0000-0002-5985-6490 AD - Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. yweom@yonsei.ac.kr. FAU - Park, Sang Wook AU - Park SW AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Lee, Ji Hyun AU - Lee JH AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Son, Jung-Woo AU - Son JW AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Youn, Young Jin AU - Youn YJ AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Ahn, Min-Soo AU - Ahn MS AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Ahn, Sung-Gyun AU - Ahn SG AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Kim, Jang-Young AU - Kim JY AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Lee, Seung-Hwan AU - Lee SH AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. FAU - Yoon, Junghan AU - Yoon J AD - Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, Korea. LA - eng GR - NRF- 2017R1D1A1A02019212/Basic Science Research Program through the National Research Foundation of Korea (NRF)/ GR - NRF-2016M3A9B4919711/Bio & Medical Technology Development Program of the NRF funded by the Korean government, the Ministry of Science, ICT & Future Planning/ PT - Journal Article DEP - 20190422 PL - Netherlands TA - Mol Cell Biochem JT - Molecular and cellular biochemistry JID - 0364456 RN - 0 (IFNG protein, human) RN - 0 (Muscle Proteins) RN - 82115-62-6 (Interferon-gamma) RN - 8DUH1N11BX (Tryptophan) RN - XD0FY1J13B (1-methyltryptophan) SB - IM MH - Autophagy/drug effects MH - Cell Cycle Checkpoints/*drug effects MH - Fibrosis MH - Gene Expression Regulation/drug effects MH - Humans MH - Interferon-gamma/*pharmacology MH - Muscle Proteins/biosynthesis MH - Myocardial Infarction/drug therapy/*metabolism/pathology MH - Myocardium/*metabolism/pathology MH - Myofibroblasts/*metabolism/pathology MH - Signal Transduction/drug effects MH - Tryptophan/*analogs & derivatives/pharmacology PMC - PMC6616223 OTO - NOTNLM OT - Apoptosis OT - Indoleamine 2,3-dioxygenase OT - Interferon-gamma OT - Myofibroblast COIS- The authors declare that they have no conflict of interest. EDAT- 2019/04/23 06:00 MHDA- 2019/07/19 06:00 PMCR- 2019/04/22 CRDT- 2019/04/23 06:00 PHST- 2018/07/05 00:00 [received] PHST- 2019/02/23 00:00 [accepted] PHST- 2019/04/23 06:00 [pubmed] PHST- 2019/07/19 06:00 [medline] PHST- 2019/04/23 06:00 [entrez] PHST- 2019/04/22 00:00 [pmc-release] AID - 10.1007/s11010-019-03542-7 [pii] AID - 3542 [pii] AID - 10.1007/s11010-019-03542-7 [doi] PST - ppublish SO - Mol Cell Biochem. 2019 Aug;458(1-2):197-205. doi: 10.1007/s11010-019-03542-7. Epub 2019 Apr 22.