NF-κB/AP-1-targeted inhibition of macrophage-mediated inflammatory responses by depigmenting compound AP736 derived from natural 1,3-diphenylpropane skeleton.
AP736 was identified as an antimelanogenic drug that can be used for the prevention of melasma, freckles, and dark spots in skin by acting as a suppressor of melanin synthesis and tyrosinase expression. Since macrophage-mediated inflammatory responses are critical for skin health, here we investigated the potential anti-inflammatory activity of AP736. The effects of AP736 on various inflammatory events such as nitric oxide (NO)/prostaglandin (PG) E2 production, inflammatory gene expression, phagocytic uptake, and morphological changes were examined in RAW264.7 cells. AP736 was found to strongly inhibit the production of both NO and PGE2 in lipopolysaccharide- (LPS-) treated RAW264.7 cells. In addition, AP736 strongly inhibited both LPS-induced morphological changes and FITC-dextran-induced phagocytic uptake. Furthermore, AP736 also downregulated the expression of multiple inflammatory genes, such as inducible NO synthase (iNOS), cyclooxygenase- (COX-) 2, and interleukin- (IL-) 1β in LPS-treated RAW264.7 cells. Transcription factor analysis, including upstream signalling events, revealed that both NF-κB and AP-1 were targeted by AP736 via inhibition of the IKK/IκBα and IRAK1/TAK1 pathways. Therefore, our results strongly suggest that AP736 is a potential anti-inflammatory drug due to its suppression of NF-κB-IKK/IκBα and AP-1-IRAK1/TAK1 signalling, which may make AP736 useful for the treatment of macrophage-mediated skin inflammation.
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Van Thai
VT
Ha
Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
Heung Soo
HS
Beak
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Eunji
E
Kim
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 ; Department of Animal Science, Patuakhali Science and Technology University, Patuakhali 8602, Bangladesh.
Muhammad Jahangir
MJ
Hossen
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Woo Seok
WS
Yang
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Yong
Y
Kim
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Jun Ho
0000-0002-0609-2474
JH
Kim
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Sungjae
0000-0002-5513-5135
S
Yang
Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
Jeong-Hwan
0000-0002-0109-1739
JH
Kim
Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
Yung Hyup
YH
Joo
Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
Chang Seok
CS
Lee
Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
Joonho
J
Choi
Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
Hong-Ju
HJ
Shin
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Sungyoul
S
Hong
Medical Beauty Research Institute, AmorePacific R&D Center, Yongin 446-729, Republic of Korea.
Song Seok
SS
Shin
Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
Jae Youl
0000-0001-8141-9927
JY
Cho
D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D008543:Melanins / Q000096:biosynthesis; D051379:Mice; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D012880:Skin Pigmentation / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*
C000592311:5-adamantan-1-yl-N-(2,4-dihydroxybenzyl)-2,4-dimethoxybenzamide; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008543:Melanins; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D052247:Nitric Oxide Synthase Type II; D000218:Adamantane