Inhibition of LPS-induced inflammatory mediators by 3-hydroxyanthranilic acid in macrophages through suppression of PI3K/NF-κB signaling pathways.
Many tryptophan metabolites have immunomodulatory effects on various immune cells. 3-Hydroxyanthranilic Acid (3-HAA) is a tryptophan metabolite reported to have anti-inflammatory activity. The mechanism of this activity is unclear. The present study examined the immunomodulatory effects and molecular mechanisms of 3-HAA on macrophages. Pretreatment of 3-HAA (0.1-10 μg mL(-1)) for 2 h markedly inhibited NO and cytokine production in LPS-stimulated Raw 264.7 cells. Moreover, translocation and activation of NF-κB by LPS in the nucleus were abrogated through the prevention of IκB degradation by 3-HAA treatment. 3-HAA significantly suppressed LPS-induced PI3K/Akt/mTOR activation, whereas MAPKs were not affected by 3-HAA treatment. Furthermore, the inhibition of mTOR by 3-HAA resulted in decreased production of inflammatory mediators and NF-κB activity. Similar results were also observed in primary peritoneal macrophages. Furthermore, 3-HAA modulated macrophage polarization. Collectively, the results suggest that 3-HAA has an immunomodulatory effect that may result from inhibition of PI3K/Akt/mTOR and NF-κB activation, thereby decreasing the production of pro-inflammatory mediators.
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea. snpyo@skku.edu.
Kyoungran
K
Lee
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea. snpyo@skku.edu.
Jong-Hwan
JH
Kwak
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea. snpyo@skku.edu.
Suhkneung
S
Pyo
D015095:3-Hydroxyanthranilic Acid / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D018836:Inflammation Mediators / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
D015095:3-Hydroxyanthranilic Acid; D016207:Cytokines; D018836:Inflammation Mediators; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse