Spilanthol Inhibits COX-2 and ICAM-1 Expression via Suppression of NF-κB and MAPK Signaling in Interleukin-1β-Stimulated Human Lung Epithelial Cells
Spilanthol a phytochemical derived from the Spilanthes acmella plant has antimicrobial, antioxidant, and anti-inflammatory properties. This study evaluated its effects on the expression of intercellular adhesion molecule 1 (ICAM-1) and inflammation-related mediators in IL-1β-stimulated human lung epithelial A549 cells. Human lung epithelial A549 cells were pretreated with various concentrations of spilanthol (3–100 μM) followed by treatment with IL-1β to induce inflammation. The protein levels of pro-inflammatory cytokines, chemokines, and prostaglandin E2 (PGE2) were measured using ELISA. Cyclooxygenase-2 (COX-2), heme oxygenase (HO-1), nuclear transcription factor kappa-B (NF-κB), and mitogen-activated protein kinase (MAPK) were measured by immunoblotting. The mRNA expression levels of ICAM-1 and MUC5AC were determined by real-time polymerase chain reaction. Spilanthol decreased the expression of PGE2, COX-2, TNF-α, and MCP-1. It also decreased ICAM-1 expression and suppressed monocyte adhesion to IL-1β-stimulated A549 cells. Spilanthol also significantly inhibited the phosphorylation of MAPK and I-κB. These results suggest that spilanthol exerts anti-inflammatory effects by inhibiting the expression of the pro-inflammatory cytokines, COX-2, and ICAM-1 by inhibiting the NF-κB and MAPK signaling pathways.
KEY WORDSchemokines ICAM-1 MAPK NF-κB spilanthol
Wen-Chung Huang and Ling-Yu Wu designed the study and performed the experiments. Sindy Hu searched the literature and performed the experiments. Shu-Ju analyzed interpretation of data and drafting the manuscript.
This study was supported in part by grants from the Chang Gung Memorial Hospital (CMRPF1G0201), the Ministry of Science and Technology in Taiwan (MOST 105-2320-B-255-004), and Chang Gung University of Science and Technology (EZRPF3FG0071).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
- 2.Gao, P., P.G. Gibson, K.J. Baines, I.A. Yang, J.W. Upham, P.N. Reynolds, S. Hodge, A.L. James, C. Jenkins, M.J. Peters, J. Zhang, and J.L. Simpson. 2015. Anti-inflammatory deficiencies in neutrophilic asthma: Reduced galectin-3 and IL-1RA/IL-1β. Respiratory Research 16: 5. https://doi.org/10.1186/s12931-014-0163-5.CrossRefPubMedPubMedCentralGoogle Scholar
- 6.Min, J.K., Y.M. Kim, S.W. Kim, M.C. Kwon, Y.Y. Kong, and I.K. Hwang. 2005. TNF-related activation-induced cytokine enhances leukocyte adhesiveness: Induction of ICAM-1 and VCAM-1 via TNF receptor-associated factor and protein kinase C-dependent NF-B activation in endothelial cells. Journal of Immunology 175 (1): 531–540.CrossRefGoogle Scholar
- 7.Hoesel, B. Schmid, J. A. 2013. The complexity of NF-κB signaling in inflammation and cancer. https://doi.org/10.1186/1476-4598-12-86.
- 15.Liu, W., Q. Liang, S. Balzar, S. Wenzel, M. Gorska, and R. Alam. 2008. Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic airways. The Journal of Allergy and Clinical Immunology 12 (4): 893–902.CrossRefGoogle Scholar
- 18.Wu, L.C., N.C. Fan, M.H. Lin, I.R. Chu, S.J. Huang, C.Y. Hu, and S.Y. Han. 2008. Anti-inflammatory effect of spilanthol from Spilanthes acmella on murine macrophage by down regulating LPS-induced inflammatory mediators. Journal of Agricultural and Food Chemistry 56 (7): 2341–2349.CrossRefPubMedGoogle Scholar
- 20.Yumi, Y., and B.G. Richard. 2001. Therapeutic potential of inhibition of the NF-κB pathway in the treatment of inflammation and cancer. The Journal of Clinical Investigation 107 (2): 35–42.Google Scholar
- 21.Richter, E., K. Ventz, M. Harms, J. Mostertz, and F. Hochgräfe. 2016. Induction of macrophage function in human THP-1 cells is associated with rewiring of MAPK signaling and activation of MAP3K7 (TAK1) protein kinase. Frontiers in Cell and Development Biology. https://doi.org/10.3389/fcell.2016.00021.
- 22.Moldoveanu, B., P. Otmishi, P. Jani, J. Walker, X. Sarmiento, J. Guardiola, M. Saad, and Y. Jerry. 2009. Inflammatory mechanisms in the lung. Inflammation Research 2 (16): 1–11.Google Scholar
- 23.I-Ta, L. 2013. Chuen-Mao, Y. Inflammatory signalings involved in airway and pulmonary diseases. Mediat Inflamm. Article ID 791231,12 pagesGoogle Scholar
- 25.Suter, P.M., S. Suter, E. Girardin, P. Roux-Lombard, G.E. Grau, and J.M. Dayer. 1992. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. The American Review of Respiratory Disease 145 (5): 1016–1022.CrossRefPubMedGoogle Scholar
- 28.Kevin, S., D. Delphine, M.C. Megan, M. Elisabeth, and G. Philippe. 2011. The traditional medicine Spilanthes acmella, and the alkylamides spilanthol and undeca-2E -ene -8,10-diynoic acid isobutylamide, demonstrate in vitro and in vivo anti-malarial activity. Phytotherapy Research 25 (7): 1098–1101.CrossRefGoogle Scholar