Browsing by Author "Hsiao, Ya-Wen"

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Interactions of host IL-6 and IFN-gamma and cancer-derived TGF-beta 1 on MHC molecule expression during tumor spontaneous regression
(2008-07-01)
Hsiao, Ya-Wen
;
Liao, Kuang-Wen
;
Chung, Tien-Fu
;
Liu, Chen-Hsuan
;
Hsu, Chia-Da
Many tumors down-regulate major histocompatibility complex (MHC) antigen expression to evade host immune surveillance. However, there are very few in vivo models to study MHC antigen expression during tumor spontaneous regression. In addition, the roles of transforming growth factor beta1 (TGF-beta 1), interferon gamma (IFN-gamma), and interleukin (IL)-6 in modulating MHC antigen expression are ill understood. We previously reported that tumor infiltrating lymphocyte (TIL)-derived IL-6 inhibits TGF-beta 1 and restores natural killing (NK) activity. Using an in vivo canine-transmissible venereal tumor (CTVT) tumor model, we presently assessed IL-6 and TGF-beta involvement associated with the MHC antigen expression that is commonly suppressed in cancers. IL-6, IFN-gamma, and TGF-beta 1, closely interacted with each other and modulated MHC antigen expression. In the presence of tumor-derived TGF-beta 1, host IFN-gamma from TIL was not active and, therefore, there was low expression of MHC antigen during tumor progression. TGF-beta 1-neutralizing antibody restored IFN-gamma-activated MHC antigen expression on tumor cells. The addition of exogenous IL-6 that has potent anti-TGF-beta 1 activity restored IFN-gamma activity and promoted MHC antigen expression. IFN-gamma and IL-6 in combination acted synergistically to enhance the expression of MHC antigen. Thus, the three cytokines, IL-6, TGF-beta 1, and IFN-gamma, closely interacted to modulate the MHC antigen expression. Furthermore, transcription factors, including STAT-1, STAT-3, IRF-1, NF-kappa B, and CREB, were significantly elevated after IL-6 and IFN-gamma treatment. We conclude that the host IL-6 derived from TIL works in combination with host IFN-gamma to enhance MHC molecule expression formerly inhibited by TGF-beta 1, driving the tumor toward regression. It is suggested that the treatment of cancer cells that constitutively secrete TGF-beta 1 should incorporate anti-TGF-beta activity. The findings in this in vivo tumor regression model have potential applications in cancer immunotherapy.
Interleukin-17 enhances cardiac ventricular remodeling via activating MAPK pathway in ischemic heart failure
(2018-09-01)
Chang, Shih-Lin
;
Hsiao, Ya-Wen
;
Tsai, Yung-Nan
;
Lin, Shien-Fong
;
Liu, Shuen-Hsin
Background: We aimed to investigate the impact of interleukin (IL)-17 on ventricular remodeling and the genesis of ventricular arrhythmia (VA) in an ischemic heart failure (HF) model. The expression of the proinflammatory cytokine IL-17 is upregulated during myocardial ischemia and plays a fundamental role in post-infarct inflammation. However, the influence of IL-17 on the genesis of VA has not yet been studied. Methods and results: The level of inflammation and Th17 cell (CD4(+)IL-17(+)) expression in the rabbit model of ischemic HF were studied by flow cytometry, quantitative polymerase chain reaction (qPCR), and enzyme-linked immunosorbent assay (ELISA). The effect of IL-17 on VA induction following acute and chronic administration of IL-17 was determined using electrophysiological techniques and optical mapping. The expression of IL-17 target genes and related cytokines and chemokines in vivo and in vitro were measured using qPCR, ELISA, and immunoblotting. Th17 cells were markedly increased in the ischemic HF rabbit model. IL-17 directly induced VA in vivo and in vitro in a dose-dependent manner. IL-17 decreased conduction velocity, lengthened action potential duration, and increased the slope of the left ventricle (LV) restitution curve. IL-17 treatment led to fibrosis, collagen production and apoptosis in the LV. Furthermore, increased IL-17 signaling activated mitogen-activated protein kinase and increased the expression of downstream target genes, IL-6, TNF, CCL20, and CXCL1. An anti IL -17 neutralizing antibody abolished the effects of IL-17. Conclusions: The expression of IL-17 and its downstream target genes may play fundamental roles in inducing VA in ischemic HF.