Presence of membrane-bound TGF-beta1 and its regulation by IL-2-activated immune cell-derived IFN-gamma in head and neck squamous cell carcinoma cell lines.
The presence of membrane-bound TGF-beta1 (mTGF-beta1) has been recently observed in regulatory T cells, but only a few studies have reported the same phenomenon in cancer cells. In this study, we investigate the regulation of mTGF-beta1 expression in five head and neck squamous cell carcinoma cell lines using FACS analysis. Through blocking Ab and exogenous cytokine treatment experiments, we found that expression of mTGF-beta1 is significantly induced by the activated immune cell-derived factor IFN-gamma. In addition, IFN-gamma and TNF-alpha are shown to have a synergistic effect on mTGF-beta1 expression. Moreover, we found that exogenous TNF-alpha induces endogenous TNF-alpha mRNA expression in an autocrine loop. In contrast to previous reports, we confirm that, in this model, mTGF-beta1 is neither a rebound form of once-secreted TGF-beta1 nor an activated form of its precursor membrane latency-associated peptide. Inhibitors of transcription (actinomycin D), translation (cycloheximide), or membrane translocation (brefeldin A) effectively block the induction of mTGF-beta1, which suggests that induction of mTGF-beta1 by IFN-gamma and/or TNF-alpha occurs through de novo synthesis. These findings suggest that some cancer cells can detect immune activating cytokines, such as IFN-gamma and TNF-alpha, and actively block antitumor immunity by induction of mTGF-beta1.
Ahn
Yong-Oon
YO
Cancer Research Institute, Innovative Research Institute for Cell Therapy, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Lee
June-Chul
JC
Sung
Myung-Whun
MW
Heo
Dae Seog
DS
D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006258:Head and Neck Neoplasms / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D017077:Culture Media, Conditioned; D007376:Interleukin-2; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma