Nordihydroguaiaretic acid inhibits IFN-γ-induced STAT tyrosine phosphorylation in rat brain astrocytes

• Published in: Biochemical and biophysical research communications 2005-03, Vol.328 (2), p.595-600
• Main Authors: Jeon, Sae-Bom, Ji, Kyung-Ae, You, Hye-Jin, Kim, Jae-Hong, Jou, Ilo, Joe, Eun-hye
• Format: Article
• Language: English
• Subjects: 5-Lipoxygenase; Animals; Arachidonate 5-Lipoxygenase - immunology; Arachidonate 5-Lipoxygenase - metabolism; Astrocytes - drug effects; Astrocytes - immunology; Astrocytes - metabolism; Brain - drug effects; Brain - immunology; Brain - metabolism; Cells, Cultured; Dose-Response Relationship, Drug; Inflammation; Interferon-gamma - pharmacology; Interferon-γ; Lipoxygenase Inhibitors; Masoprocol - pharmacology; Microglia - drug effects; Microglia - immunology; Microglia - metabolism; NDGA; Phosphorylation - drug effects; Rats; Rats, Sprague-Dawley; Signal Transduction - drug effects; Signal Transduction - physiology; STAT; Trans-Activators - immunology; Trans-Activators - metabolism; Tyrosine - immunology; Tyrosine - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.01.025

The Janus kinase (JAK) and signal transducers and activators of transcription (STAT) signal cascades are major pathways that mediate the inflammatory functions of interferon-γ (IFN-γ), an important pro-inflammatory cytokine. Therefore, regulation of JAK/STAT signaling should modulate IFN-γ-mediated inflammation. In this study, we found that nordihydroguaiaretic acid (NDGA), a well-known lipoxygenase (LO) inhibitor, suppressed IFN-γ-induced inflammatory responses in brain astrocytes. In the presence of NDGA, interferon regulatory factor-1 expression was significantly reduced. Expression of monocyte chemotactic protein-1 and interferon-gamma inducible protein-10 mRNA in response to IFN-γ was significantly suppressed in the presence of NDGA, as was tyrosine-phosphorylation of JAK and STAT. However, the 5-LO products, leukotriene B 4 (LTB 4) and leukotriene C 4, were not detected in cells treated with IFN-γ, indicating that the effect of NDGA seemed to be independent of 5-LO inhibition. In addition, two other 5-LO inhibitors (Rev5901 and AA861) did not mimic the effect of NDGA, and the 5-LO metabolites, 5-hydroxyeicosatetraenoic acid and LTB 4, were unable to reverse NDGA-driven suppression of STAT activation or affect basal STAT phosphorylation. Taken together, these results suggest that NDGA regulates IFN-γ-mediated inflammation through mechanisms unrelated to the inhibition of 5-LO.