Role of STAT3 and Pl 3-Kinase/Akt in mediating the survival actions of cytokines on sensory neurons

The binding of cytokines to the gp130 receptor activates the STAT3, MEK/MAP K, and PI3K/Akt signalling pathways. To assess the relative importance of t hese pathways in promoting the survival of cytokine-dependent neurons, we c onditionally inactivated STAT3 in mice an inhibited MEK, PI3K, and Akt in c ultured neurons using pharmacological reagents and by expressing specific i nhibitory proteins. Inactivation of STAT3 enhanced the death of the cytokin e-dependent sensory neurons of the nodose ganglion in vivo and substantiall y reduced the response of these neurons to CNTF and LIF in vitro. LY294002, an inhibitor of PI3K, but not PD98059, an inhibitor of MEK, markedly reduc ed the response of these neurons to CNTF, as did dominant-negative PI3K, do minant-negative Akt, and overexpression of Ruk(1) (a natural PI3K inhibitor ). These results demonstrate that STAT3 and PI3K/Akt signalling play major roles in mediating the survival response of neurons to cytokines.