Abstract
Ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), and oncostatin M (OSM) belong to the Interleukin-6 cytokine family, and utilize the receptor subunit gp130 for initiating signal transmission. These cytokines are likely to promote neuronal survival and axonal regeneration after peripheral nerve injury, but molecular mechanisms how they act on neurons remain to be elucidated. In this study, recombinant CNTF, LIF, CT-1, and OSM (5-500 ng/ml) significantly enhanced survival and neurite outgrowth of cultured adult rat dorsal root ganglion (DRG) neurons. Among these recombinant proteins at the same concentration (50 ng/ml), CNTF showed the highest activity on the ratios of survival and neurite-bearing cells. By Western blot analysis, CNTF induced phosphorylation of signal transducer and activator of transcription (STAT) 3, Akt and extracellular signal regulated kinase (ERK) in the neurons. The neurite outgrowth-promoting activity of CNTF was diminished by co-treatment with 5-25 μM of Janus family of tyrosine kinase (JAK) 2 inhibitor AG490, 25-50 μM of phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor LY294002, or 50 μM of mitogen-activated protein kinase kinase (MEK) inhibitor PD98059. Its survival-promoting activity was also affected by AG490 and LY294002, but not by PD98059. These findings suggest that JAK2-STAT3, PI3K-Akt and MEK/ERK signaling pathways are involved in the CNTF-induced neurite outgrowth in mature DRG neurons, whereas the former two pathways may play major roles in mediating the survival response of neurons to CNTF. [J Physiol Sci. 2008;58 Suppl:S36]
