Inducers of oxidative stress block ciliary neurotrophic factor activation of Jak/STAT signaling in neurons

Abstract

Generation of reactive oxygen species (ROS) with the accumulation of oxidative damage has been implicated in neurodegenerative disease and in the degradation of nervous system function with age. Here we report that ROS inhibit the activity of ciliary neurotrophic factor (CNTF) in nerve cells. Treatment with hydrogen peroxide (H 2 O 2 ) as a generator of ROS inhibited CNTF-mediated Jak/STAT signaling in all cultured nerve cells tested, including chick ciliary ganglion neurons, chick neural retina, HMN-1 motor neuron hybrid cells, and SH-SY5Y and BE(2)-C human neuroblastoma cells. H 2 O 2 treatment of non-neuronal cells, chick skeletal muscle and HepG2 hepatoma cells, did not inhibit Jak/STAT signaling. The H 2 O 2 block of CNTF activity was seen at concentrations as low as 0.1 mM and within 15 min, and was reversible upon removal of H 2 O 2 from the medium. Also, two other mediators of oxidative stress, nitric oxide and rotenone, inhibited CNTF signaling. Treatment of neurons with H 2 O 2 and rotenone also inhibited interferon-c-mediated activation of Jak/STAT1. Depleting the intracellular stores of reduced glutathione by treatment of BE(2)-C cells with nitrofurantoin inhibited CNTF activity, whereas addition of reduced glutathione protected cells from the effects of H 2 O 2 . These results suggest that disruption of neurotrophic factor signaling by mediators of oxidative stress may contribute to the neuronal damage observed in neurodegenerative diseases and significantly affect the utility of CNTF-like factors as therapeutic agents in preventing nerve cell death. Keywords: ciliary neurotrophic factor, cytokine, gpl30, reactive oxygen species, signal transduction, tyrosine kinase. Signaling through the ciliary neurotrophic factor (CNTF) receptor has been implicated in the development, survival and maintenance of a broad range of neurons and glia in the PNS and CNS, as well as cardiac and skeletal muscle. CNTF receptors are essential for embryonic development and the receptor knockout phenotype in mice is embryonic lethal (DeChiara et al. 1995). Defects in CNTF expression result in an impaired neural injury response in mice (Masu et al. 1993;Yao et al. 1999;Linker et al. 2002) and decreased neuron numbers in embryonic chick (Ernsberger et al. 1989;Finn et al. 1998). In addition, a variety of neuronal, glial and muscle cell types show responses to CNTF in vivo or in vitro affecting neuronal phenotype, neurotransmitter receptor levels, neurotransmitter release, metabolism and survival (Adler et al.

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

“…A site-directed mutagenesis experiment revealed that cysteine residues, Cys866 and Cys917, act as a redox-sensitive switch controlling the catalytic activity of Jak2 (29). However, there are inconsistencies regarding changes in Jak2 activity under oxidized conditions in previous reports (30,31). Research has suggested that Jak2 activity in response to oxidative stress may also be dependent on the cell line used, due to difference in structural elements of Jak2 (29).…”

Neurotrophic Effects of Leukemia Inhibitory Factor on Neural Cells Derived from Human Embryonic Stem Cells

“…Both LIF and ciliary neurotrophic factor (CNTF) are members of the Il-6 cytokine family, they are structurally related and share common receptor component subunits [62]. CNTF has neuroprotective properties but cannot prevent oxidative damage in cells exposed to H 2 O 2 [63]. Thus LIF may be effective in controlling damage by in vitro ROS inducers.…”

Garcinol, a Polyisoprenylated Benzophenone Modulates Multiple Proinflammatory Signaling Cascades Leading to the Suppression of Growth and Survival of Head and Neck Carcinoma

“…3D). Because ROS generation blocks STAT3 signaling (23,33,34) and garcinol was found to induce ROS production in CAL27 cells, we next determined whether MTG, a well-known ROS scavenger, could restore the inhibitory effect of garcinol on STAT3 activation. For this, CAL27 cells were pretreated with 10 mmol/L antioxidant MTG for 120 minutes and were then subjected to 120-minute incubation with 25 mmol/L garcinol.…”