Hyperthermia enhances CD95-ligand gene expression in T lymphocytes.
Hyperthermia represents an interesting therapeutic strategy for the treatment of tumors. Moreover, it is able to regulate several aspects of the immune response. Fas (APO-1/CD95) and its ligand (FasL) are cell surface proteins whose interaction activates apoptosis of Fas-expressing targets. In T cells, the Fas-Fas-L system regulates activation-induced cell death, is implicated in diseases in which lymphocyte homeostasis is compromised, and plays an important role during cytotoxic and regulatory actions mediated by these cells. In this study we describe the effect of hyperthermia on activation of the fas-L gene in T lymphocytes. We show that hyperthermic treatment enhances Fas-L-mediated cytotoxicity, fas-L mRNA expression, and fas-L promoter activity in activated T cell lines. Our data indicate that hyperthermia enhances the transcriptional activity of AP-1 and NF-kappaB in activated T cells, and this correlates with an increased expression/nuclear translocation of these transcription factors. Moreover, we found that heat shock factor-1 is a transactivator of fas-L promoter in activated T cells, and the overexpression of a dominant negative form of heat shock factor-1 may attenuate the effect of hyperthermia on fas-L promoter activity. Furthermore, overexpression of dominant negative mutants of protein kinase Cepsilon (PKCepsilon) and PKCtheta; partially inhibited the promoter activation and, more importantly, could significantly reduce the enhancement mediated by hyperthermia, indicating that modulation of PKC activity may play an important role in this regulation. These results add novel information on the immunomodulatory action of heat, in particular in the context of its possible use as an adjuvant therapeutic strategy to consider for the treatment of cancer.
Cippitelli
Marco
M
Department of Experimental Medicine and Pathology, Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Viale Regina Elena 324, 00161 Rome, Italy. marco.cippitelli@uniroma1.it
Fionda
Cinzia
C
Di Bona
Danilo
D
Piccoli
Mario
M
Frati
Luigi
L
Santoni
Angela
A
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D003601:Cytotoxicity Tests, Immunologic; D004268:DNA-Binding Proteins / Q000378:metabolism; D053222:Fas Ligand Protein; D005334:Fever / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D000076249:Heat Shock Transcription Factors; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection
D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D000076249:Heat Shock Transcription Factors; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D011493:Protein Kinase C