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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1448-1455
Downregulation of Interleukin-12 (IL-12) Responsiveness in Human T
Cells by Transforming Growth Factor- : Relationship
With IL-12 Signaling
Cécile Pardoux,
Xiaojing Ma,
Stéphanie Gobert,
Sandra Pellegrini,
Patrick Mayeux,
Françoise Gay,
Giorgio Trinchieri, and
Salem Chouaib
From the Laboratoire Cytokines et Immunologie des Tumeurs Humaines,
INSERM U487, Institut Gustave Roussy, Villejuif; INSERM U363,
Hôpital Cochin, Paris; INSERM U276, Institut Pasteur, Paris,
France; and The Wistar Institute, Philadelphia, PA.
Interleukin-12 (IL-12) is a cytokine that plays a central role in
the control of cell-mediated immunity. We have previously shown that
transforming growth factor- 1 (TGF-) inhibitory effects on human
primary allogeneic cytotoxicity and proliferative responses interfere
with IL-12 pathway. The present study was undertaken to further
elucidate the biochemical basis of the functional interaction between
these two cytokines and to define the site of TGF- action on the
signaling pathway activated by IL-12. Our data indicate that TGF-
induced an inhibition of interferon- (IFN-) production without
affecting the IL-12R1 and IL-12R2 subunits mRNA expression by
activated T cells. We further show that TGF- has a significant inhibitory effect on the early signal transduction events following interaction of IL-12 with its receptor on activated T cells, resulting in the inhibition of both JAK2 and Tyk2 phosphorylation. In addition, TGF- was found to significantly inhibit IL-12-induced
phosphorylation of the STAT4 transcription factor. Electrophoretic
mobility shift assay indicated that TGF- induced a decrease in
IL-12-induced STAT4 DNA binding activity in T lymphocytes. This study
suggests that TGF- influences IL-12 responsiveness at least in part
by inhibiting early signaling events essential to gene induction in
IL-12-activated T cells.
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