Nordihydroguaiaretic acid inhibits IFN-gamma-induced STAT tyrosine phosphorylation in rat brain astrocytes.
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.
Jeon
Sae-Bom
SB
Interdisciplinary Course for Neuroscience and Technology, Ajou University School of Medicine, Suwon 442-721, South Korea.
Ji
Kyung-Ae
KA
You
Hye-Jin
HJ
Kim
Jae-Hong
JH
Jou
Ilo
I
Joe
Eun-Hye
EH
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*
D016859:Lipoxygenase Inhibitors; D015534:Trans-Activators; D014443:Tyrosine; D009637:Masoprocol; D007371:Interferon-gamma; D001094:Arachidonate 5-Lipoxygenase