ABSTRACT
Recent studies have demonstrated that bone marrow stromal cells can undergo adipogenesis or osteoblastogenesis in vivo, and in vitro, and that peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a central role in the control of adipocyte differentiation. In the present study, we treated a murine stromal cell line (TMS-14) with a cocktail of dexamethasone, insulin and glucose (DIG cocktail), which caused the cells to convert to fat-laden cells with adipocyte-like morphology. We also exposed TMS-14 cells to DIG cocktail followed by 15-deoxy Delta(12,14)-prostaglandin J2 (15d-PGJ2), a ligand of PPAR gamma, interleukin- 11 (IL-11), 9-cis retinoic acid (9-cis RA) and vitamin K2. 15d-PGJ2 enhanced DIG cocktail-induced adipogenesis, whereas IL-11, 9-cis RA and vitamin K2 each inhibited adipogenesis induced by DIG cocktail. The gene expressions of four adipogenesis markers, PPAR gamma 2, adipocyte P2 (aP2), adipocyte determination and differentiation factor 1 (ADD1), and fatty acid synthase (FAS) were enhanced by DIG cocktail and these expressions were more enhanced by 15d-PGJ2, in contrast they were attenuated by 9-cis RA. IL-11 also attenuated the adipogenesis markers except ADD1. Western blotting showed that 15d-PGJ2 enhanced the levels of PPAR gamma, C/EBP alpha and RXR alpha proteins, while IL-11 and 9-cis RA decreased the level of PPAR gamma protein, but not C/EBP alpha protein and vitamin K2 decreased the level of C/EBP alpha protein. We also tested the effect of 15d-PGJ2 on osteoblastogenesis, using TMS-12 cells, another stromal cell clone from the same mouse, which differentiate into osteoblasts spontaneously. 15d-PGJ2 did not affect osteoblastogenesis, as detected by von Kossa staining and Cbfa-1 gene expression. These data indicate that 15d-PGJ2 enhances the expression of both PPAR gamma and C/EBP alpha and as a result it stimulates adipogenesis in murine bone marrow cells.
Subject(s)
Adipocytes/metabolism , Neoplasm Proteins , Prostaglandin D2/analogs & derivatives , Prostaglandin D2/pharmacology , Stromal Cells/metabolism , Transcription, Genetic/drug effects , Adipocytes/cytology , Alitretinoin , Animals , Biomarkers/analysis , CCAAT-Enhancer-Binding Protein-alpha/biosynthesis , Cell Differentiation , Cell Line , Interleukin-11/pharmacology , Mice , Osteoblasts/metabolism , RNA, Messenger/biosynthesis , Receptors, Cytoplasmic and Nuclear/biosynthesis , Receptors, Cytoplasmic and Nuclear/genetics , Stromal Cells/cytology , Stromal Cells/drug effects , Transcription Factors/biosynthesis , Transcription Factors/genetics , Tretinoin/pharmacology , Vitamin K 2/pharmacologyABSTRACT
Recientemente, se ha demostrado que la manifestación de inmunidad antitumoral resulta de las interacciones entre varias poblaciones celulares del sistema inmune. La inmunoterapia con interleucina-2 (IL-2) y células destructoras de linfocinas activadas generadas por linfocitos análogos ha producido regresiones significativas en tumore de pacientes con cáncer avanzado. El efecto mitogénico de la IL-2 en linfocitos T citolíticos de tumores-reactivos (CTL), destructores naturales y LAK puede incrementar el potencial de defensa en la expansión de tumores. A diferencia del tratamiento sistémico, la administración de IL-2 en la vecindad del tumor puede ofrecer ciertas ventajas, tales como: uso de dosis bajas y menos anticuerpos anti IL-2 y proveer un cambio de confrontación mucho mejor con inhibidores IL-2 y mecanismos de retroalimentación, los cuales podrán limitar sustancialmente los posibles efectos terapéuticos de la IL-2 en pacientes con tumores
