title: Nordihydroguaiaretic acid inhibits IFN-gamma-induced STAT tyrosine phosphorylation in rat brain astrocytes.
abstract: The Janus kinase (JAK) and signal transducers and activators of transcription (STAT) signal cascades are major pathways that mediate the inflammatory functions of interferon-gamma (IFN-gamma), an important pro-inflammatory cytokine. Therefore, regulation of JAK/STAT signaling should modulate IFN-gamma-mediated inflammation. In this study, we found that nordihydroguaiaretic acid (NDGA), a well-known lipoxygenase (LO) inhibitor, suppressed IFN-gamma-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-gamma 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-gamma, 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-gamma-mediated inflammation through mechanisms unrelated to the inhibition of 5-LO.
authors.affiliation: Interdisciplinary Course for Neuroscience and Technology, Ajou University School of Medicine, Suwon 442-721, South Korea.
authors.forename: Sae-Bom
authors.initials: SB
authors.lastname: Jeon
authors.forename: Kyung-Ae
authors.initials: KA
authors.lastname: Ji
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: You
authors.forename: Jae-Hong
authors.initials: JH
authors.lastname: Kim
authors.forename: Ilo
authors.initials: I
authors.lastname: Jou
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Joe
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000276:immunology / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D007371:Interferon-gamma / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors; D009637:Masoprocol / Q000494:pharmacology*; D017628:Microglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism*; D014443:Tyrosine / Q000276:immunology / Q000378:metabolism*
chemical_list: D016859:Lipoxygenase Inhibitors; D015534:Trans-Activators; D014443:Tyrosine; D009637:Masoprocol; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase