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Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages.
Int Immunopharmacol. 2017 Aug; 49:21-29.II

Abstract

Although xanthotoxin has been reported to possess skin-protective and anti-oxidative properties, its anti-inflammatory capacity has not been studied to date. Therefore, we investigated this role as well as the molecular mechanisms of xanthotoxin in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Xanthotoxin inhibited production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) by the LPS-induced macrophages in a concentration-dependent manner. It also suppressed the LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression at the protein levels and iNOS, COX-2, TNF-α, and IL-6 at the mRNA levels. At a molecular level, the effects were related to xanthotoxin-mediated attenuation of the LPS-induced transcriptional and DNA-binding activity of activator protein-1 (AP-1). This attenuation was associated with decreased phosphorylation of c-Fos, but not c-Jun. Xanthotoxin also displayed a suppressive effect on the transcriptional and DNA-binding activity of nuclear transcription factor kappa-B (NF-κB) by inhibiting p65 nuclear translocation. In addition, xanthotoxin significantly reduced the phosphorylation at signal transducers and activators of transcription 1 (STAT1, Ser 727 and Tyr 701) and STAT3 (Tyr 705), as well as Janus kinase (JAK) 1 and 2 in LPS-induced RAW 264.7 macrophages. Finally, xanthotoxin suppressed the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK). Taken together, these results indicate that xanthotoxin decreases NO, PGE2, TNF-α, and IL-6 production by downregulation of the NF-κB, AP-1, and JAK/STAT signaling pathways in LPS-induced 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.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

28550731

Citation

Lee, Seung-Bin, et al. "Xanthotoxin Suppresses LPS-induced Expression of iNOS, COX-2, TNF-α, and IL-6 Via AP-1, NF-κB, and JAK-STAT Inactivation in RAW 264.7 Macrophages." International Immunopharmacology, vol. 49, 2017, pp. 21-29.
Lee SB, Lee WS, Shin JS, et al. Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages. Int Immunopharmacol. 2017;49:21-29.
Lee, S. B., Lee, W. S., Shin, J. S., Jang, D. S., & Lee, K. T. (2017). Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages. International Immunopharmacology, 49, 21-29. https://doi.org/10.1016/j.intimp.2017.05.021
Lee SB, et al. Xanthotoxin Suppresses LPS-induced Expression of iNOS, COX-2, TNF-α, and IL-6 Via AP-1, NF-κB, and JAK-STAT Inactivation in RAW 264.7 Macrophages. Int Immunopharmacol. 2017;49:21-29. PubMed PMID: 28550731.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6 via AP-1, NF-κB, and JAK-STAT inactivation in RAW 264.7 macrophages. AU - Lee,Seung-Bin, AU - Lee,Woo Seok, AU - Shin,Ji-Sun, AU - Jang,Dae Sik, AU - Lee,Kyung Tae, Y1 - 2017/05/24/ PY - 2017/03/08/received PY - 2017/05/16/revised PY - 2017/05/19/accepted PY - 2017/5/28/pubmed PY - 2018/5/2/medline PY - 2017/5/28/entrez KW - Activator protein-1 KW - Janus kinase-signal transducers and activators of transcription KW - Nuclear factor-κB KW - Xanthotoxin SP - 21 EP - 29 JF - International immunopharmacology JO - Int Immunopharmacol VL - 49 N2 - Although xanthotoxin has been reported to possess skin-protective and anti-oxidative properties, its anti-inflammatory capacity has not been studied to date. Therefore, we investigated this role as well as the molecular mechanisms of xanthotoxin in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Xanthotoxin inhibited production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) by the LPS-induced macrophages in a concentration-dependent manner. It also suppressed the LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression at the protein levels and iNOS, COX-2, TNF-α, and IL-6 at the mRNA levels. At a molecular level, the effects were related to xanthotoxin-mediated attenuation of the LPS-induced transcriptional and DNA-binding activity of activator protein-1 (AP-1). This attenuation was associated with decreased phosphorylation of c-Fos, but not c-Jun. Xanthotoxin also displayed a suppressive effect on the transcriptional and DNA-binding activity of nuclear transcription factor kappa-B (NF-κB) by inhibiting p65 nuclear translocation. In addition, xanthotoxin significantly reduced the phosphorylation at signal transducers and activators of transcription 1 (STAT1, Ser 727 and Tyr 701) and STAT3 (Tyr 705), as well as Janus kinase (JAK) 1 and 2 in LPS-induced RAW 264.7 macrophages. Finally, xanthotoxin suppressed the LPS-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (MAPK). Taken together, these results indicate that xanthotoxin decreases NO, PGE2, TNF-α, and IL-6 production by downregulation of the NF-κB, AP-1, and JAK/STAT signaling pathways in LPS-induced RAW 264.7 macrophages. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/28550731/Xanthotoxin_suppresses_LPS_induced_expression_of_iNOS_COX_2_TNF_α_and_IL_6_via_AP_1_NF_κB_and_JAK_STAT_inactivation_in_RAW_264_7_macrophages_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(17)30194-7 DB - PRIME DP - Unbound Medicine ER -