Regulatory effects of transforming growth factor-beta on IL-2- and IL-4-dependent T cell-cycle progression.
Previous studies suggested that the potent immunosuppressive activities of transforming growth factor-beta (TGF-beta) were mediated in part through the inhibition of IL-2-dependent S-phase progression and mitosis of activated T cells. To further investigate the mechanism of T cell growth inhibition by TGF-beta, two constitutively activated murine T cell clones were employed as defined model systems for the growth factor-dependent phase of T cell proliferation. The Th cell line, HT-2, proliferated in response to either IL-2 or IL-4, whereas the cytotoxic T cell line, CT6, exhibited strict dependence on IL-2 for growth stimulation. In both cell lines, picomolar concentrations of TGF-beta inhibited S-phase progression stimulated by IL-2 or IL-4. TGF-beta pretreatment decreased the expression of high affinity IL-2R on HT-2 cells, but not on CT6 cells. In contrast, IL-2-stimulated transferrin receptor expression was markedly inhibited by TGF-beta in both T cell lines. Analyses of growth factor-dependent specific mRNA accumulation revealed that TGF-beta exerted selective inhibitory effects on gene expression in HT-2 and CT6 cells. TGF-beta significantly reduced early (1 to 2 h) increases in c-myc mRNA levels stimulated by IL-2 or IL-4 in both cell lines. In HT-2 cells, TGF-beta pretreatment also inhibited the early increase in granulocyte-macrophage CSF mRNA stimulated by IL-2 or IL-4. The inhibition of c-myc and granulocyte-macrophage cyte-macrophage CSF gene expression by TGF-beta was explained, at least in part, by suppression of the growth factor-dependent transcriptional activation of these genes. These studies suggest that inhibition of c-myc gene transcription may play a fundamental role in the antiproliferative effect of TGF-beta on IL-2- or IL-4-stimulated T cells.
Department of Immunology, Mayo Clinic, Rochester, MN 55905.
J J
JJ
Ruegemer
S N
SN
Ho
J A
JA
Augustine
J W
JW
Schlager
M P
MP
Bell
D J
DJ
McKean
R T
RT
Abraham
D015152:Blotting, Northern; D002453:Cell Cycle / Q000187:drug effects*; D003115:Colony-Stimulating Factors / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006131:Growth Inhibitors; D006133:Growth Substances / Q000235:genetics; D007376:Interleukin-2 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008222:Lymphokines / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D015291:Transforming Growth Factors / Q000494:pharmacology*
D003115:Colony-Stimulating Factors; D006131:Growth Inhibitors; D006133:Growth Substances; D007376:Interleukin-2; D008222:Lymphokines; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin; D015847:Interleukin-4; D015291:Transforming Growth Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor