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Cnidilide, an alkylphthalide isolated from the roots of Cnidium officinale, suppresses LPS-induced NO, PGE2, IL-1β, IL-6 and TNF-α production by AP-1 and NF-κB inactivation in RAW 264.7 macrophages.
Int Immunopharmacol 2016; 40:146-155II

Abstract

Cnidilide, an alkyl phthalide isolated from the rhizome of Cnidium officinale, has been reported to possess antispasmodic and sedative effects. However, the anti-inflammatory capacity and molecular mechanism of cnidilide have not been studied to date. In the present study, we investigated the inhibitory effects of cnidilide on LPS-induced pro-inflammatory mediators and the underlying molecular mechanisms in RAW 264.7 macrophages. Our results indicated that cnidilide potently inhibits inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression at the protein and mRNA levels and their promoter activities, causing attendant decreases in the production of nitric oxide (NO) and prostaglandin E2 (PGE2). In addition, cnidilide reduced LPS-induced production and mRNA expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in a dose-dependent manner. Molecular data revealed that cnidilide inhibited LPS-induced transcriptional activity of activator protein-1 (AP-1) by reducing the phosphorylation and nuclear translocation of c-Fos and c-Jun. In addition, cnidilide attenuated LPS-induced transcriptional activity of nuclear factor-κB (NF-κB), and this reduction was accompanied by parallel reduction in the phosphorylation, but not in the translocation of p65 NF-κB. In addition, cnidilide inhibited LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and mitogen- and stress-activated protein kinase 1(MSK-1), a downstream kinase. Moreover, the phosphorylation of c-Jun N-terminal kinase (JNK) was suppressed by cnidilide in a concentration-dependent manner, whereas it did not inhibit the extracellular signal-regulated kinase (ERK) phosphorylation in LPS-stimulated RAW 264.7 macrophages. Taken together, our findings suggest that cnidilide has anti-inflammatory properties by inhibiting p38 MAPK, JNK, AP-1, and the NF-κB pathway in LPS-stimulated RAW 264.7 macrophages.

Authors+Show Affiliations

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea.Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea.Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea. Electronic address: ktlee@khu.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27591413

Citation

Lee, Woo-Seok, et al. "Cnidilide, an Alkylphthalide Isolated From the Roots of Cnidium Officinale, Suppresses LPS-induced NO, PGE2, IL-1β, IL-6 and TNF-α Production By AP-1 and NF-κB Inactivation in RAW 264.7 Macrophages." International Immunopharmacology, vol. 40, 2016, pp. 146-155.
Lee WS, Shin JS, Jang DS, et al. Cnidilide, an alkylphthalide isolated from the roots of Cnidium officinale, suppresses LPS-induced NO, PGE2, IL-1β, IL-6 and TNF-α production by AP-1 and NF-κB inactivation in RAW 264.7 macrophages. Int Immunopharmacol. 2016;40:146-155.
Lee, W. S., Shin, J. S., Jang, D. S., & Lee, K. T. (2016). Cnidilide, an alkylphthalide isolated from the roots of Cnidium officinale, suppresses LPS-induced NO, PGE2, IL-1β, IL-6 and TNF-α production by AP-1 and NF-κB inactivation in RAW 264.7 macrophages. International Immunopharmacology, 40, pp. 146-155. doi:10.1016/j.intimp.2016.08.021.
Lee WS, et al. Cnidilide, an Alkylphthalide Isolated From the Roots of Cnidium Officinale, Suppresses LPS-induced NO, PGE2, IL-1β, IL-6 and TNF-α Production By AP-1 and NF-κB Inactivation in RAW 264.7 Macrophages. Int Immunopharmacol. 2016;40:146-155. PubMed PMID: 27591413.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cnidilide, an alkylphthalide isolated from the roots of Cnidium officinale, suppresses LPS-induced NO, PGE2, IL-1β, IL-6 and TNF-α production by AP-1 and NF-κB inactivation in RAW 264.7 macrophages. AU - Lee,Woo-Seok, AU - Shin,Ji-Sun, AU - Jang,Dae Sik, AU - Lee,Kyung-Tae, Y1 - 2016/09/01/ PY - 2016/05/24/received PY - 2016/08/16/revised PY - 2016/08/19/accepted PY - 2016/9/4/pubmed PY - 2017/5/4/medline PY - 2016/9/4/entrez KW - Activator protein-1 KW - Cnidilide KW - Mitogen- and stress-activated protein kinase 1 KW - Nitric oxide KW - Nuclear factor-κB KW - Prostaglandin E(2) SP - 146 EP - 155 JF - International immunopharmacology JO - Int. Immunopharmacol. VL - 40 N2 - Cnidilide, an alkyl phthalide isolated from the rhizome of Cnidium officinale, has been reported to possess antispasmodic and sedative effects. However, the anti-inflammatory capacity and molecular mechanism of cnidilide have not been studied to date. In the present study, we investigated the inhibitory effects of cnidilide on LPS-induced pro-inflammatory mediators and the underlying molecular mechanisms in RAW 264.7 macrophages. Our results indicated that cnidilide potently inhibits inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression at the protein and mRNA levels and their promoter activities, causing attendant decreases in the production of nitric oxide (NO) and prostaglandin E2 (PGE2). In addition, cnidilide reduced LPS-induced production and mRNA expression of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in a dose-dependent manner. Molecular data revealed that cnidilide inhibited LPS-induced transcriptional activity of activator protein-1 (AP-1) by reducing the phosphorylation and nuclear translocation of c-Fos and c-Jun. In addition, cnidilide attenuated LPS-induced transcriptional activity of nuclear factor-κB (NF-κB), and this reduction was accompanied by parallel reduction in the phosphorylation, but not in the translocation of p65 NF-κB. In addition, cnidilide inhibited LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and mitogen- and stress-activated protein kinase 1(MSK-1), a downstream kinase. Moreover, the phosphorylation of c-Jun N-terminal kinase (JNK) was suppressed by cnidilide in a concentration-dependent manner, whereas it did not inhibit the extracellular signal-regulated kinase (ERK) phosphorylation in LPS-stimulated RAW 264.7 macrophages. Taken together, our findings suggest that cnidilide has anti-inflammatory properties by inhibiting p38 MAPK, JNK, AP-1, and the NF-κB pathway in LPS-stimulated RAW 264.7 macrophages. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/27591413/Cnidilide_an_alkylphthalide_isolated_from_the_roots_of_Cnidium_officinale_suppresses_LPS_induced_NO_PGE2_IL_1β_IL_6_and_TNF_α_production_by_AP_1_and_NF_κB_inactivation_in_RAW_264_7_macrophages_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(16)30339-3 DB - PRIME DP - Unbound Medicine ER -