The dietary flavonoid Kaempferol mediates anti-inflammatory responses via the Src, Syk, IRAK1, and IRAK4 molecular targets.
Even though a lot of reports have suggested the anti-inflammatory activity of kaempferol (KF) in macrophages, little is known about its exact anti-inflammatory mode of action and its immunopharmacological target molecules. In this study, we explored anti-inflammatory activity of KF in LPS-treated macrophages. In particular, molecular targets for KF action were identified by using biochemical and molecular biological analyses. KF suppressed the release of nitric oxide (NO) and prostaglandin E2 (PGE2), downregulated the cellular adhesion of U937 cells to fibronectin (FN), neutralized the generation of radicals, and diminished mRNA expression levels of inflammatory genes encoding inducible NO synthase (iNOS), TNF-α, and cyclooxygenase- (COX-) 2 in lipopolysaccharide- (LPS-) and sodium nitroprusside- (SNP-) treated RAW264.7 cells and peritoneal macrophages. KF reduced NF-κB (p65 and p50) and AP-1 (c-Jun and c-Fos) levels in the nucleus and their transcriptional activity. Interestingly, it was found that Src, Syk, IRAK1, and IRAK4 responsible for NF-κB and AP-1 activation were identified as the direct molecular targets of KF by kinase enzyme assays and by measuring their phosphorylation patterns. KF was revealed to have in vitro and in vivo anti-inflammatory activity by the direct suppression of Src, Syk, IRAK1, and IRAK4, involved in the activation of NF-κB and AP-1.
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Shi Hyoung
SH
Kim
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Jae Gwang
JG
Park
Department of Dermatological Health Management, Eulji University, Seongnam, Republic of Korea.
Jongsung
J
Lee
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Woo Seok
WS
Yang
Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Gye Won
GW
Park
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Han Gyung
HG
Kim
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Young-Su
0000-0002-7166-3659
YS
Yi
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Kwang-Soo
KS
Baek
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Nak Yoon
0000-0001-8814-8701
NY
Sung
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea ; Department of Animal Science, Patuakhali Science and Technology University, Patuakhali 8602, Bangladesh.
Muhammad Jahangir
MJ
Hossen
Department of Food and Nutrition, School of Food Service Industry, Chungkang College of Cultural Industries, Icheon 467-744, Republic of Korea.
Mi-Nam
MN
Lee
Department of Veterinary Physiology, College of Veterinary Medicine, Biosafety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea.
Jong-Hoon
JH
Kim
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Jae Youl
0000-0001-8141-9927
JY
Cho
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D002467:Cell Nucleus / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D044949:Kaempferols / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D000072377:Syk Kinase; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020298:U937 Cells
D000893:Anti-Inflammatory Agents; D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; D044949:Kaempferols; D008070:Lipopolysaccharides; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C006552:kaempferol; D052247:Nitric Oxide Synthase Type II; D011505:Protein-Tyrosine Kinases; D016392:Proto-Oncogene Proteins pp60(c-src); C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; C507774:Irak4 protein, mouse