SLAM activation induces ERK and CREB phosphorylation that leads to IFN-γ production during active tuberculosis (TB) (45.27)

Abstract IFN-γ is crucial for protection against M. tuberculosis (Mtb). Previously we reported that signaling through SLAM on Mtb-stimulated cells induced CREB activation increasing IFN-γ. Here, we deeply investigated the potential relationship between SLAM-CREB and IFN-γ. After Mtb-stimulation, most of the IFN-γ+ cells co-expressed SLAM and pCREB (48,68 ± 11,18), whereas a smaller percentage of T cells expressed one of the two molecules. These results demonstrate that the induction of IFN-γ mediated by SLAM in TB depends, at least in part, on CREB activation. It was reported that SLAM signaling would induce the activation of the protein kinase Erk. To analyze the signaling pathways induced by SLAM that contribute to CREB activation and IFN-γ secretion in TB, we studied Erk phosphorylation after SLAM activation. The addition of PD90059 (an Erk inhibitor) to Mtb stimulated cells inhibited the percentage of IFN-γ+pCREB+ T cells, indicating that Erk could be involved on CREB activation. Moreover, the addition of PD90059 to Mtb±α-SLAM stimulated cells significantly decreased IFN-γ production (% inhibition: 71,6 ± 7,4). Finally, α-SLAM induced Erk activation in Mtb stimulated cells. These results demonstrate that IFN-γ production induced by SLAM signaling on Mtb stimulated cells is, at least in part, mediated by Erk and CREB phosphorylation. These data contribute new information about the molecular basis operating during SLAM activation that leads to IFN-γ production in human TB.