Cadmium blocks receptor-mediated Jak/STAT signaling in neurons by oxidative stress

Abstract

Cadmium is an environmental contaminant producing numerous pathological effects including neurological disorders. The mechanisms through which cadmium produces neurotoxicities are not completely known. We found that divalent cadmium (CdCl 2) inhibited ciliary neurotrophic factor (CNTF)-mediated Jak1 and Jak2 tyrosine kinase signaling in human BE(2)-C neuroblastoma cells. CdCl 2 concentrations as low as 0.1 μM and for times as brief as 2 h significantly reduced CNTF-induced tyrosine phosphorylation of both STAT1 and STAT3, the principle substrates of Jak kinases in neurons. The phosphorylation of STAT1 by interferon-γ was also inhibited by CdCl 2. However, activation of the fibroblast growth factor receptor tyrosine kinase was not inhibited by CdCl 2. Jak/STAT signaling was inhibited by CdCl 2 selectively in cultures of chick retina neurons and neuroblastoma cells, whereas signaling in the nonneuronal cells HepG2 and chick skeletal myotubes was not affected. Results using dichlorofluorescein indicated CdCl 2 increased cellular oxidative stress, and all of these effects of CdCl 2 were protected against by pretreatment with antioxidants. Neuronal inhibition of Jak kinase by CdCl 2-induced oxidative stress is a new mechanism of cadmium action which may directly produce neurotoxic symptoms as well as implicate cadmium and related metals as environmental factors in the etiology of neurodegenerative diseases.