D. Nandan et Ne. Reiner, TGF-BETA ATTENUATES THE CLASS-II TRANSACTIVATOR AND REVEALS AN ACCESSORY PATHWAY OF IFN-GAMMA ACTION, The Journal of immunology, 158(3), 1997, pp. 1095-1101
In the present report, the induction of the HLA-DRA gene in response t
o IFN-gamma is shown to be selectively attenuated by TGF-beta. Thus, t
he accumulation in response to IFN-gamma of mRNA for the DRA gene, but
not for the guanylate binding protein-2 gene, is markedly reduced in
the presence of TGF-beta. Moreover, the data presented show that the m
echanism by which TGF-beta inhibits expression of DRA involves attenua
tion of the class II transactivator (CIITA) gene. This conclusion is b
ased on the finding that induction of CIITA gene expression in respons
e to IFN-gamma, is completely abrogated in TGF-beta-treated cells. In
contrast, TGF-beta did not affect IFN-gamma-induced tyrosine phosphory
lation of Jak1, Jak2, or the signal transducer and activator of transc
ription-1. (Stat1). TGF-beta also did not inhibit the appearance of IF
N-gamma-activated, Stat1 DNA-binding activity in intact cells. Thus, t
he effects of TGF-beta on CIITA could not be explained by altered sign
aling through Jak-Stat1. Potential alternative targets for the inhibit
ory effects of TGF-beta were identified in renaturation tyrosine kinas
e assays, which revealed three IFN-gamma-activated protein tyrosine ki
nases that, in contrast to the Janus kinases, are sensitive to TGF-bet
a. These findings 1) indicate that inhibition of MHC class II gene exp
ression by TGF-beta involves attenuation of the CIITA gene independent
ly of effects on Janus kinases, 2) provide direct evidence that IFN-ga
mma activates both Janus and non-Janus protein tyrosine kinases, and 3
) identify an accessory pathway of IFN-gamma, action involving tyrosin
e kinases that, unlike the Jak-Stat1 pathway, are impaired by TGF-beta
.