Resistance to TGF-beta1-mediated growth inhibition correlates with sustained Smad2 phosphorylation in primary murine splenocytes.
Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that regulates cell growth and differentiation in many types of cells. TGF-beta1 is especially known to exert a variety of regulatory functions in the immune system, such as T cell differentiation and T cell function. Signal transduction of TGF-beta1 is mediated by phosphorylation of R-Smads upon receptor activation. Hetero-oligomers of R- and Co-Smads translocate into the nucleus and regulate transcription of specific target genes. Here we describe the effect of long-term exposure to TGF-beta1 on the effector function of differentially stimulated primary murine splenocytes and purified primary murine CD8(+) cytotoxic T cells. Long-term exposure to TGF-beta1 results in non-responsiveness to TGF-beta1-induced Smad2 phosphorylation. This is seen either by no phosphorylation or sustained phosphorylation of Smad2. Furthermore, we observed a strong correlation between sustained Smad2 phosphorylation and resistance to TGF-beta1-mediated growth inhibition. In contrast, splenocyte cultures strongly growth inhibited by TGF-beta1 showed no Smad2 phosphorylation. Lytic activity of these cultures, however, was found to be suppressed regardless of proliferation properties and Smad2 phosphorylation pattern. These findings may contribute to understanding the mechanisms of how TGF-beta1 suppresses immune responses and promotes tumor progression.
Feldmann
Kristina
K
Department of Physiological Chemistry II, Biocenter, University of Würzburg, Würzburg, Germany.
Sebald
Walter
W
Knaus
Petra
P
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D013154:Spleen / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II