PMID- 26173590 OWN - NLM STAT- MEDLINE DCOM- 20160315 LR - 20191210 IS - 1423-0127 (Electronic) IS - 1021-7770 (Print) IS - 1021-7770 (Linking) VI - 22 IP - 1 DP - 2015 Jul 15 TI - Tumor necrosis factor-alpha induces VCAM-1-mediated inflammation via c-Src-dependent transactivation of EGF receptors in human cardiac fibroblasts. PG - 53 LID - 10.1186/s12929-015-0165-8 [doi] LID - 53 AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine and elevated in the regions of tissue injury and inflammatory diseases. The deleterious effects of TNF-alpha on fibroblasts may aggravate heart inflammation mediated through the up-regulation of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). However, the mechanisms underlying TNF-alpha-induced VCAM-1 expression in cardiac fibroblasts remain unknown. This study aimed to investigate the roles of TNF-alpha in VCAM-1 expression and its effects on human cardiac fibroblasts (HCFs). RESULTS: The primary culture HCFs were used in this study. The results obtained with Western blotting, real time-quantitative PCR, and promoter activity analyses showed that TNF-alpha-induced VCAM-1 expression was mediated through TNF receptor (TNFR) 1-dependent gene up-regulation. Activation of TNFR1 by TNF-alpha transactivated c-Src-dependent EGF receptor (EGFR) linking to PI3K/Akt cascade, and then led to transcriptional activity of NF-kappaB. Moreover, the results of promoter reporter assay demonstrated that the phosphorylated p65 NF-kappaB turned on VCAM-1 gene expression. Subsequently, up-regulation of VCAM-1 promoted monocytes adhesion to HCFs challenged with TNF-alpha determined by cell adhesion assay. CONCLUSIONS: Taken together, these results indicate that in HCFs, activation of NF-kappaB by c-Src-mediated transactivation of EGFR/PI3K/Akt cascade is required for TNF-alpha-induced VCAM-1 expression. Finally, increased VCAM-1 enhances monocytes adhering to HCFs challenged with TNF-alpha. Understanding the mechanisms of VCAM-1 up-regulated by TNF-alpha on HCFs may provide rationally therapeutic interventions for heart injury or inflammatory diseases. FAU - Lin, Chih-Chung AU - Lin CC AD - Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, Kwei-Shan, Tao-Yuan, Taiwan. AD - College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan. FAU - Pan, Chih-Shuo AU - Pan CS AD - Department of Physiology, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan. AD - Department of Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, Taiwan. FAU - Wang, Chen-Yu AU - Wang CY AD - Department of Physiology, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan. AD - Department of Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, Taiwan. FAU - Liu, Shiau-Wen AU - Liu SW AD - Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, Kwei-Shan, Tao-Yuan, Taiwan. AD - College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan. FAU - Hsiao, Li-Der AU - Hsiao LD AD - Department of Anesthetics, Chang Gung Memorial Hospital at Linkuo, Kwei-Shan, Tao-Yuan, Taiwan. AD - College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan. FAU - Yang, Chuen-Mao AU - Yang CM AD - Department of Physiology, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan. chuenmao@mail.cgu.edu.tw. AD - Department of Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, Taiwan. chuenmao@mail.cgu.edu.tw. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150715 PL - England TA - J Biomed Sci JT - Journal of biomedical science JID - 9421567 RN - 0 (NF-kappa B) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (Tumor Necrosis Factor-alpha) RN - 0 (Vascular Cell Adhesion Molecule-1) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.2 (CSK Tyrosine-Protein Kinase) RN - EC 2.7.10.2 (src-Family Kinases) RN - EC 2.7.10.23 (CSK protein, human) SB - IM MH - CSK Tyrosine-Protein Kinase MH - ErbB Receptors/*genetics MH - Fibroblasts/metabolism MH - Gene Expression Regulation MH - Humans MH - Inflammation/*genetics/pathology MH - Myocardium/metabolism/pathology MH - NF-kappa B/genetics MH - Phosphatidylinositol 3-Kinases MH - Primary Cell Culture MH - Receptors, Tumor Necrosis Factor, Type I/genetics MH - Transcriptional Activation/genetics MH - Tumor Necrosis Factor-alpha/*biosynthesis/genetics MH - Vascular Cell Adhesion Molecule-1/*biosynthesis/genetics MH - src-Family Kinases/*biosynthesis/genetics PMC - PMC4502472 EDAT- 2015/07/16 06:00 MHDA- 2016/03/16 06:00 PMCR- 2015/07/15 CRDT- 2015/07/16 06:00 PHST- 2015/01/08 00:00 [received] PHST- 2015/07/07 00:00 [accepted] PHST- 2015/07/16 06:00 [entrez] PHST- 2015/07/16 06:00 [pubmed] PHST- 2016/03/16 06:00 [medline] PHST- 2015/07/15 00:00 [pmc-release] AID - 10.1186/s12929-015-0165-8 [pii] AID - 165 [pii] AID - 10.1186/s12929-015-0165-8 [doi] PST - epublish SO - J Biomed Sci. 2015 Jul 15;22(1):53. doi: 10.1186/s12929-015-0165-8.