Transforming growth factor-beta inhibits human T-cell proliferation through multiple targets.
This study investigates further the inhibitory effects of transforming growth factor-beta (TGF-beta) on human T-lymphocyte responses to mitogenic stimulation. T cells were stimulated either with mitogenic concentrations of PHA or with submitogenic concentrations of Con A followed by the addition of IL-2. DNA synthesis ([3H]thymidine incorporation) in both systems was inhibited by 60-69% in the presence of TGF-beta, with maximal reduction occurring on days 4 and 5 of culture. Cell surface expression of transferrin receptor (TfR) and IL-2 receptor-alpha (p55) were inhibited by 20-80% in the Con A/rIL-2 system and 20-45% in the PHA system in the presence of TGF-beta. In addition, mitogen-induced up-regulation of TfR and IL-2R mRNA levels were inhibited by TGF-beta. Finally, we investigated the effect of TGF-beta on the assembly of clathrin monomers into assembled coated pits and vesicles, and essential step in TfR and IL-2R alpha turnover. Stimulation of T cells using either mitogen system resulted in an increase in the level of assembled clathrin, which was almost completely inhibited by TGF-beta. These findings suggest that TGF-beta may act at several sites in mitogen-mediated proliferative pathways to contribute to the inhibition of T-cell proliferation.
Fox
F E
FE
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6082.
Capocasale
R J
RJ
Ford
H C
HC
Lamb
R J
RJ
Moore
J S
JS
Nowell
P C
PC
D002966:Clathrin / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation / Q000187:drug effects*; D008934:Mitogens / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000378:metabolism; D011990:Receptors, Transferrin / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000502:physiology
D002966:Clathrin; D008934:Mitogens; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D016212:Transforming Growth Factor beta; D004247:DNA