Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 88
In T lymphocytes, ablation of STAT3 expression reinstates STAT1-dependent apoptosis
by both IFNg and IL-6
Gabriella Regis1,2, Laura Icardi1,2, Laura Conti1,2, Roberto Chiarle1, Paola
Bernabei1, Valeria Poli1 and Francesco Novelli1,2
1Center for Experimental Research and Medical Studies (CERMS), San Giovanni
Battista Hospital, Via Santena 5, 10126, Turin, Italy and 2Department of Medicine and
Experimental Oncology, University of Turin, Corso Raffaello 30, 10125, Turin, Italy.
The Interferon gamma (IFNg)/Signal Transducer and Activator of Transcription (STAT) 1
pathway is mainly involved in the control of T lymphocytes homeostasis. However, these
cells downregulate IFNgR2 signaling chain by both ligand-dependent and ligand-independent
mechanisms and become refractory to the IFNg-mediated control of their expansion. Here, we
investigate the role of STAT3, a transcriptional factor activated by many cytokines including
IFNg, in the negative regulation of the IFNg/STAT1 signaling pathway. The expression of
STAT3 in two human malignant T cell lines, PF383 and ST4, was almost completely
inhibited by lentivirus that deliver small interfering (si) RNA against STAT3. The survival of
many neoplastic cells is dependent on STAT3 expression, whereas the viability of malignant
T cell lines we used was not influenced by STAT3 expression silencing. In T cells expressing
normal STAT3 amounts, either IFNg or IL-6 induced a weak activation of STAT1. By
contrast, in the absence of STAT3 both IFNg and IL-6 dependent STAT1 activation was
enhanced. This increased activation of STAT1 by IL-6 confirms previous data that showed
that this cytokine activates STAT1 and mediates an IFNg-like response in cells lacking
STAT3. As STAT1 regulates the expression of many genes involved in the control of cellular
proliferation and/or apoptosis we checked the proliferative responses to IFNg or IL-6 in T cell
lines where STAT3 is silenced or not, but we didn’t observe any alteration. On the contrary,
both IFNg and IL-6 switched on the apoptotic program in T cells devoid of STAT3
expression, whereas they were ineffective in cells expressing normal amounts of STAT3. The
apoptotic pathways are currently under investigation in our Laboratory. However, these data
clearly show that the combined inhibition of STAT3 synthesis and the treatment with IFNg or
IL-6 reinstate STAT1-dependent apoptosis in human T lymphocytes.
- 421 -