Dissecting the TNF-alpha/IFN-gamma induced inflammatory response in skeletal muscle cells

• Main Author: Divya Malathy Ravinath
• Other Authors: YOU, REN-IN
• Format: Others
• Language: en_US
• Published: 2019
• Online Access: http://ndltd.ncl.edu.tw/handle/c6zty8

碩士 === 慈濟大學 === 醫學生物技術碩士班 === 107 === Skeletal muscles constitute myotubes which are formed by the differentiation of their precursor cell, the myoblasts. IL-1, TNF-alpha,IFN-beta, IFN-gamma are circulating cytokines that regulate signaling pathways leading to abnormal expression of myokines during chronic inflammatory conditions. IL-15 is a myokine released from skeletal muscles (SkMCs) during muscle wasting and hypertrophy. Inflammatory myopathies are a group of diseases that cause progressive muscle weakness due to the infiltration of inflammatory cells like the CD8+ T cells in the muscle tissue. Deregulated expression of membrane bound IL-15 on the muscle myofibers have been identified from inflammatory myopathy specimens which correlates to CD8+NKG2D high T cells. Thus abnormal inflammatory responses of skeletal muscle lead to inflammatory myopathies which causes severe muscle weakness via myokine dysregulation. The aim of the study is to dissect the mechanism of inflammatory myopathy and signaling pathways involved in regulation of IL-15 during co-stimulation of TNF-alpha/IFN-gamma We found that TNF-alpha and IFN-gamma enhances IL-15/IL-15Ra lpha expression through the activation of NF-kappaB and JAK-STAT pathways. The synergism of TNF-alpha and IFN-gamma happens at the transcriptional level and the transcriptional regulation of IL-15 correlates to its protein level. Further we found that ERK plays a role as negative regulator of IL-15 and a bidirectional link between ERK and AMPK persistance. IRF1 nuclear translocation further enhances the transcriptional regulation of IL-15 and the expression of IL-15 is dependent on IRF1 expression. TNF-alpha and IFN-gamma co-stimulation enhances the complex formation of IRF1 with p65 at IL-15 promoter region to regulate its expression. Exploring the mechanism of how inflammatory cytokines synergistically affects IL-15 induction will provide the possible targets to treat inflammatory myopathies.