New class of linoleic acid metabolites biosynthesized by corn and rice lipoxygenases: suppression of proinflammatory mediator expression via attenuation of MAPK- and Akt-, but not PPARgamma-, dependent pathways in stimulated macrophages.
In response to endogenous and exogenous stimuli, macrophages are activated to produce a cocktail of proinflammatory and anti-apoptotic mediators, thereby participating in the processes of inflammation-associated oncogenesis. Cereals, including corn and rice, have biological potentials to synthesize self-protective chemicals in order to repel the invasion of microorganisms and insects. We examined the suppressive effects of several fatty acids, including a new class of lipoxygenase metabolites of linoleic acid (LA) found in cereals, namely (+/-)-9-hydroxy-trans,cis-10,12-octadecadienoic acid (9-HOA from rice), (+/-)-13-hydroxy-10-oxo-trans-11-octadecenoic acid (13-HOA from corn), and (+/-)-10-oxo-trans-11-octadecen-13-olide (10-ODO from corn), on lipopolysaccharide (LPS)-induced mRNA expression of proinflammatory mediators in RAW264.7 murine macrophages. Each metabolite exhibited a suppressive activity toward nitrite production than LA, octadeca-9Z,11E-dienoic acid (a conjugated LA), and 13S-hydroxyoctadeca-9Z,11E-dienoic acid. LPS-up-regulated mRNA expression of inducible nitric oxide synthase, cyclooxygenase (COX)-2, interleukin-6, and toll-like receptor-2, -4, and -9 was also markedly attenuated without affecting the expression levels of several constitutive genes, including COX-1, as detected by reverse transcription-polymerase chain reactions. In addition, Western blot and luciferase reporter assay results showed that 13-HOA suppressed the phosphorylation of mitogen-activated protein kinases (extracellular signal-regulated kinasel/2, c-Jun N-terminal kinasel/2, p38 mitogen-activated protein kinase), and Akt (Ser473), and also attenuated degradation of inhibitor kappaB, nuclear translocation of nuclear factor kappaB (NFkappaB), and the transcriptional activities of NFkappaB and activator protein-1, both of which have essential roles in the transcription of numerous proinflammatory and oncogenic genes. In contrast, 13-HOA did not serve as a ligand for peroxisome proliferator-activated receptor-gamma. Based on our findings, we propose that 13-HOA, a functionally novel LA-derivative, is a promising agent for anti-inflammatory and chemopreventive strategies with reasonable molecular mechanisms.
Murakami
Akira
A
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan. cancer@kais.kyoto-u.ac.jp
Nishizawa
Takashi
T
Egawa
Kahori
K
Kawada
Teruo
T
Nishikawa
Yasushi
Y
Uenakai
Kazuo
K
Ohigashi
Hajime
H
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis*; D020672:I-kappa B Proteins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D019787:Linoleic Acid / Q000378:metabolism*; D008084:Lipoxygenase / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D012275:Oryza / Q000201:enzymology*; D047495:PPAR gamma / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051195:Toll-Like Receptor 2 / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D003313:Zea mays / Q000201:enzymology*
D005231:Fatty Acids, Unsaturated; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D009573:Nitrites; D047495:PPAR gamma; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; C082486:13-hydroxy-10-oxo-11-octadecenoic acid; D019787:Linoleic Acid; D008084:Lipoxygenase; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases