Increased function and survival of IL-15-transduced human dendritic cells are mediated by up-regulation of IL-15Ralpha and Bcl-2.
It has been recently demonstrated that dendritic cells (DC) coincubated with interleukin (IL)-15 express high levels of the Bcl-2 family of proteins and display an increased resistance to tumor-induced apoptotic death. Here, the phenotype, functions, and survival of human DC transduced with adenoviral vector encoding the human IL-15 gene were studied. The transduction of DC with the IL-15 gene resulted in a significant elevation of expression of CD83, CD86, and CD40 molecules, which was blocked by anti-IL-15 monoclonal antibodies. This effect was also accompanied by an increased production of IL-12 and stimulated ability of DC to induce T cell proliferation. Furthermore, transduction of DC with the IL-15 gene significantly increased their resistance to prostate cancer-induced apoptosis: Overexpression of IL-15 on DC blocked tumor-induced inhibition of Bcl-2 expression and prolonged DC survival after coincubation with tumor cells. Finally, overexpression of IL-15 in DC was associated with a higher level of expression of IL-15 receptor alpha chain mRNA. In summary, these results suggest that transduction of DC with the IL-15 gene markedly stimulates DC function and protects them from tumor-induced apoptosis.
Tourkova
Irina L
IL
Department of Pathology, University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute, Pennsylvania 15213, USA.
Yurkovetsky
Zoya R
ZR
Gambotto
Andrea
A
Makarenkova
Valeria P
VP
Perez
Lori
L
Balkir
Levent
L
Robbins
Paul D
PD
Shurin
Michael R
MR
Shurin
Galina V
GV
D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis; D051940:B7-2 Antigen; D019013:CD40 Antigens / Q000096:biosynthesis; D002470:Cell Survival; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000235:genetics* / Q000502:physiology; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000097802:CD83 Antigen
D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; D007136:Immunoglobulins; D018664:Interleukin-12; D019409:Interleukin-15; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D000097802:CD83 Antigen; C497964:CD86 protein, human; C508024:IL15RA protein, human