Re. Curiel et al., Bryostatin-1 and IL-2 synergize to induce IFN-gamma expression in human peripheral blood T cells: Implications for cancer immunotherapy, J IMMUNOL, 167(9), 2001, pp. 4828-4837
Bryostatin-1 (Bryo-1), a protein kinase C modulator with antineoplastic act
ivity, may exert some of its antitumor activity through activation of the i
mmune response. Studies in tumor-bearing hosts have indicated that the T ce
ll response, particularly IFN-gamma production, is impaired. To evaluate wh
ether Bryo-1 plus IL-2 may affect the activation pattern of T cells, we inv
estigated the expression of IFN-gamma mRNA and protein in human primary T c
ells. Northern blot analysis and ELISAs demonstrated that Bryo-1 and IL-2 s
ynergized to induce both IFN-gamma mRNA and protein expression. This synerg
istic induction was seen within 3 h of treatment and with as little as 10 U
/ml IL-2 and 1.0 ng/ml Bryo-1. In vitro transcription assays revealed that
Bryo-1 plus IL-2 induced transcriptional activation of the IFN-gamma gene.
Furthermore, mRNA stability studies indicated that this treatment also enha
nced the IFN-gamma mRNA half-life. Both CD4(+) and CD8(+) T cells responded
to the treatment with IFN-gamma expression. The induction of the IFN-gamma
expression was decreased by a specific p38 mitogen-activated protein kinas
e inhibitor, but not by a protein kinase C inhibitor. Our results demonstra
te for the first time that Bryo-1 in combination with IL-2 control IFN-gamm
a gene expression at both the transcriptional and post-transcriptional leve
ls through a p38 mitogen-activated protein kinase-dependent process. Given
the pivotal role that IFN-gamma plays in the orchestration of an effective
Th1 type of response, our results suggest that Bryo-1 plus IL-2 may be a va
luable combined therapy for cancer treatment.