Retrograde activation of STAT3 by leukemia inhibitory factor in sympathetic neurons

Leukemia inhibitory factor (LIF) is a member of the interleukin-6 family of cytokines and signals through the glycoprotein 130 and LIF receptor beta subunits. Binding of cytokines to these subunits activates multiple signaling cascades, including the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) pathway. We used compartmentalized cultures of sympathetic neurons and immunocytochemical analyses of STAT3 to examine the mechanisms involved in retrograde signaling of LIF from distal neurites (DN) to cell bodies. Addition of LIF to the DN of these neurons triggers the activation and nuclear translocation of STAT3. Inhibition of Jak activity in the cell bodies prevented LIF-induced retrograde activation of STAT3, while block of Jak activity in the DN had no effect on the appearance of activated STAT3 in the nucleus. These results show that the transport of activated Jak is not the main mechanism mediating retrograde signaling. Although there is an increase in phosphorylated STAT3 in the neurites after distal stimulation, the transport of activated STAT3 is not necessary for retrograde signaling. Our results are consistent with a signaling endosome model for retrograde signaling, in which the LIF/glycoprotein 130/LIF receptor/Jak complex is internalized and transported to activate STAT3 in the cell body.