Suppressor of Cytokine Signaling-3 Suppresses the Ability of Activated Signal Transducer and Activator of Transcription-3 to Stimulate Neurite Growth in Rat Primary Sensory Neurons

Abstract

The actions of the neuropoietic cytokines are mediated by the gp130 receptor, which activates several signaling molecules including the transcription factor STAT3 (signal transducer and activator of transcription), which, in turn, is subject to feedback inhibition by SOCS3 (suppressor of cytokine signaling). Activation of the gp130 receptor has been implicated in axonal growth particularly during regeneration, but the specific contribution of STAT3 is the subject of conflicting reports. Measurements of SOCS3 mRNA in rat dorsal root ganglia showed a significant induction in this inhibitory molecule after peripheral nerve injury. The functions of STAT3 and SOCS3 in adult rat primary sensory neurons were investigated in vitro through transduction of lentiviruses yielding a conditionally activated STAT3, native SOCS3, or a mutant SOCS3 with dominant-negative actions. The SOCS3 construct was effective in inhibiting tyrosine phosphorylation of STAT3 in a neuroblastoma cell line and in blocking nuclear accumulation of endogenous STAT3 or of the conditionally activated STAT3 chimera in primary sensory neurons. In such neurons, transduction and activation of STAT3 enhanced neurite growth, transduction with SOCS3 reduced neurite outgrowth, and transduction with mutant SOCS3 enhanced neurite growth, at least under basal conditions. In conclusion, STAT3 signaling is beneficial to axonal growth through activating transcription of unidentified genes, and SOCS3 is detrimental to axonal growth through inhibition of STAT3 and/or other transcription factors.

Ready, STAT, go: transcription factors on the move

“…This is in contrast to previous reports showing that transduction of an active STAT3 increases neurite outgrowth (Miao et al, 2006) and central DRG branches (Bareyre et al, 2011) and that deletion of STAT3 leads to reduced neurite outgrowth and sensory neuron regeneration (Qiu et al, 2005;Bareyre et al, 2011). These differences may result from the type of assays used to assess axon outgrowth and regeneration.…”

Pleiotropic regulation of macrophage polarization and tumorigenesis by formyl peptide receptor-2

“…Activated STAT3 induces the expression of suppressor of cytokine signaling-3 (SOCS3), which subsequently inhibits STAT3 signaling feedback (Miao et al, 2006). To test whether FPR2 agonists and M-CSF þ MCP-1 affected STAT3 activity in macrophages, U937 cells were incubated with LXA 4 , SAA, M-CSF þ MCP-1 and/or NSC74859 (a STAT3-specific inhibitor).…”

NFIL3 and cAMP Response Element-Binding Protein Form a Transcriptional Feedforward Loop that Controls Neuronal Regeneration-Associated Gene Expression

“…Other regeneration-associated TFs may be subject to similar negative regulatory control mechanisms. For instance, suppressor of cytokine signaling-3 (SOCS3) is upregulated by injured DRG neurons, and negatively regulates STAT3 function and neurite outgrowth (Miao et al, 2006). Clearly, further insight into transcription regulatory network interactions is indispensable for our understanding of how neuronal regeneration is regulated at the level of gene expression.…”