Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5138833 | Journal of Trace Elements in Medicine and Biology | 2017 | 7 Pages |
Abstract
One consequence of lipopolysaccharide (LPS)-induced stimulation of macrophages is the release of Interferon (IFN)-β, and subsequently the activation of the JAK-STAT1 pathway, resulting in the expression of inducible nitric oxide synthase (iNOS). Free intracellular zinc ions (Zn2+) have a profound impact as a second messenger in LPS-dependent gene expression. Previous work had indicated a Zn2+-dependent upregulation of STAT1 mRNA in response to LPS and IFN-β, potentially affecting STAT1-dependent downstream signaling upon pre-incubation with these agents. The aim of the present study was to investigate the long-term influence of Zn2+ chelation on cellular STAT1 levels and their effect on protein levels and activity of iNOS. The LPS- and IFN-β-mediated increase of STAT1 mRNA and protein levels was abrogated by chelation of Zn2+ with the membrane permeable chelator N,N,Nâ²,Nâ²-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) in RAW 264.7 macrophages. After 48 h pre-incubation together with IFN-β, TPEN also led to reduced nitric monoxide formation in response to a second stimulation with LPS. Nonetheless, the latter was observed regardless of any pre-incubation with IFN-β, suggesting that the effect of treatment with TPEN negatively affects iNOS induction independently from cellular STAT1 levels. In conclusion, long term Zn2+ chelation does affect STAT1 protein expression, but interferes with NO production by a different, yet unknown pathway not involving STAT1. However, as there are many additional STAT1-dependent genes, there might still be effects on targets other than iNOS.
Related Topics
Physical Sciences and Engineering
Chemistry
Analytical Chemistry
Authors
Cathleen Reiber, Anne Brieger, Gabriela Engelhardt, Silke Hebel, Lothar Rink, Hajo Haase,