title: Biaryl amide compounds reduce the inflammatory response in macrophages by regulating Dectin-1.
abstract: Macrophages are archetypal innate immune cells that play crucial roles in the recognition and phagocytosis of invading pathogens, which they identify using pattern recognition receptors (PRRs). Dectin-1 is essential for antifungal immune responses, recognizing the fungal cellular component β-glucan, and its role as a PRR has been of increasing interest. Previously, we discovered and characterized a novel biaryl amide compound, MPS 03, capable of inhibiting macrophage phagocytosis of zymosan. Therefore, in this study we aimed to identify other biaryl amide compounds with greater effectiveness than MPS 03, and elucidate their cellular mechanisms. Several MPS 03 derivatives were screened, four of which reduced zymosan phagocytosis in a similar manner to MPS 03. To establish whether such phagocytosis inhibition influenced the production of inflammatory mediators, pro-inflammatory cytokine and nitric oxide (NO) levels were measured. The production of TNF-α, IL-6, IL-12, and NO was significantly reduced in a dose-dependent manner. Moreover, the inflammation-associated MAPK signaling pathway was also affected by biaryl amide compounds. To investigate the underlying cellular mechanism, PRR expression was measured. MPS 03 and its derivatives were found to inhibit zymosan phagocytosis by decreasing Dectin-1 expression. Furthermore, when macrophages were stimulated by zymosan after pretreatment with biaryl amide compounds, downstream transcription factors such as NFAT, AP-1, and NF-κB were downregulated. In conclusion, biaryl amide compounds reduce zymosan-induced inflammatory responses by downregulating Dectin-1 expression. Therefore, such compounds could be used to inhibit Dectin-1 in immunological experiments and possibly regulate excessive inflammatory responses.
authors.affiliation: Host Defense Modulation Laboratory, College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 156-756, Republic of Korea.
authors.forename: Kyeong Eun
authors.initials: KE
authors.lastname: Hyung
authors.affiliation: Host Defense Modulation Laboratory, College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 156-756, Republic of Korea.
authors.forename: Mi Ji
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Host Defense Modulation Laboratory, College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 156-756, Republic of Korea.
authors.forename: Yun-Jung
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 156-756, Republic of Korea.
authors.forename: Do Ik
authors.initials: DI
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 156-756, Republic of Korea.
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Min
authors.affiliation: Pharmacognosy Laboratory, College of Pharmacy, Dankook University, San#29, Anseo-dong, Dongnam-gu, Cheonan-si, Chungnam 330-714, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Park
authors.affiliation: College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 156-756, Republic of Korea. Electronic address: khmin@cau.ac.kr.
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Min
authors.affiliation: Host Defense Modulation Laboratory, College of Pharmacy, Chung-Ang University, 221 Heukseok-dong, Dongjak-gu, Seoul 156-756, Republic of Korea. Electronic address: khwang@cau.ac.kr.
authors.forename: Kwang Woo
authors.initials: KW
authors.lastname: Hwang
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D015054:Zymosan; D000099181:Dectin-1
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D037181:Lectins, C-Type; D020928:Mitogen-Activated Protein Kinases; D009569:Nitric Oxide; D015054:Zymosan; D000099181:Dectin-1
keywords: Biaryl amide compounds; Dectin-1; Inflammation; RAW 264.7