Decursinol Angelate Inhibits LPS-Induced Macrophage Polarization through Modulation of the NFκB and MAPK Signaling Pathways

Inflammation is considered the root cause of various inflammatory diseases, including cancers. Decursinol angelate (DA), a pyranocoumarin compound obtained from the roots of Angelica gigas, has been reported to exhibit potent anti-inflammatory effects. In this study, the anti-inflammatory effects of DA on the MAP kinase and NFκB signaling pathways and the expression of pro-inflammatory cytokines were investigated in phorbol 12-myristate 13-acetate (PMA)-activated human promyelocytic leukemia (HL-60) and lipopolysaccharide (LPS)-stimulated macrophage (Raw 264.7) cell lines. PMA induced the activation of the MAP kinase-NFκB pathway and the production of pro-inflammatory cytokines in differentiated monocytes. Treatment with DA inhibited the activation of MAP kinases and the translocation of NFκB, and decreased the expression and exogenous secretion of IL-1β and IL-6. Furthermore, LPS-stimulated Raw 264.7 cells were found to have increased expression of M1 macrophage-associated markers, such as NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS), and the M2 macrophage-associated marker CD11b. LPS also activated pro-inflammatory cytokines and Erk-NFκB. Treatment with DA suppressed LPS-induced macrophage polarization and the inflammatory response by blocking Raf-ERK and the translocation of NFκB in Raw 264.7 cells. Treatment with DA also inhibited the expression of pro-inflammatory cytokines, such as IL-1β and IL-6, NOX, and iNOS in Raw 264.7 cells. These results suggest that DA has the potential to inhibit macrophage polarization and inflammation by blocking the activation of pro-inflammatory signals. These anti-inflammatory effects of DA may contribute to its potential use as a therapeutic strategy against various inflammation-induced cancers.

[1]  A. Shehzad,et al.  Decursin and decursinol angelate: molecular mechanism and therapeutic potential in inflammatory diseases , 2018, Inflammation Research.

[2]  Y. De Launoit,et al.  All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-α and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer , 2017, Mediators of inflammation.

[3]  D. Standley,et al.  TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a , 2017, Nucleic acids research.

[4]  H. Rafa,et al.  Overview of cytokines and nitric oxide involvement in immuno-pathogenesis of inflammatory bowel diseases. , 2016, World journal of gastrointestinal pharmacology and therapeutics.

[5]  Ning Wang,et al.  The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases , 2016, Oxidative medicine and cellular longevity.

[6]  C. McDonald,et al.  Characterization of M1/M2 Tumour-Associated Macrophages (TAMs) and Th1/Th2 Cytokine Profiles in Patients with NSCLC , 2016, Cancer Microenvironment.

[7]  E. Yeh,et al.  Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy , 2016, npj Breast Cancer.

[8]  In-geun Ryoo,et al.  NRF2 Signaling Negatively Regulates Phorbol-12-Myristate-13-Acetate (PMA)-Induced Differentiation of Human Monocytic U937 Cells into Pro-Inflammatory Macrophages , 2015, PloS one.

[9]  Xiaojing Li,et al.  The role of tumor-associated macrophages in breast carcinoma invasion and metastasis. , 2015, International journal of clinical and experimental pathology.

[10]  I. Müller,et al.  Metabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages , 2014, Front. Immunol..

[11]  N. Itano,et al.  Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment , 2014, Cancers.

[12]  S. Gordon,et al.  The M1 and M2 paradigm of macrophage activation: time for reassessment , 2014, F1000prime reports.

[13]  Seong-ho Lee,et al.  The Involvement of Endoplasmic Reticulum Stress in the Suppression of Colorectal Tumorigenesis by Tolfenamic Acid , 2013, Cancer Prevention Research.

[14]  Yanyong Yang,et al.  Whole Body Irradiation Induces Cutaneous Dendritic Cells Depletion via NF-κB Activation , 2013, Cellular Physiology and Biochemistry.

[15]  David W Williams,et al.  Lipopolysaccharide-Induced M2 to M1 Macrophage Transformation for IL-12p70 Production Is Blocked by Candida albicans Mediated Up-Regulation of EBI3 Expression , 2013, PloS one.

[16]  Yibin Kang,et al.  The metastasis-promoting roles of tumor-associated immune cells , 2013, Journal of Molecular Medicine.

[17]  Stephen Safe,et al.  Inhibition of rhabdomyosarcoma cell and tumor growth by targeting specificity protein (Sp) transcription factors , 2013, International journal of cancer.

[18]  Alberto Mantovani,et al.  Macrophage plasticity and polarization: in vivo veritas. , 2012, The Journal of clinical investigation.

[19]  Alyssa D Gregory,et al.  Tumor-associated neutrophils: new targets for cancer therapy. , 2011, Cancer research.

[20]  M. Abdelrahim,et al.  Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice , 2011, Investigational New Drugs.

[21]  K. Suk,et al.  Decursinol angelate blocks transmigration and inflammatory activation of cancer cells through inhibition of PI3K, ERK and NF-kappaB activation. , 2010, Cancer letters.

[22]  P. Gimotty,et al.  Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. , 2010, The Journal of clinical investigation.

[23]  T. Wei,et al.  Induction of inducible nitric oxide synthase increases the production of reactive oxygen species in RAW264.7 macrophages. , 2010, Bioscience reports.

[24]  Yeong Shik Kim,et al.  Decursin and decursinol inhibit VEGF-induced angiogenesis by blocking the activation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. , 2009, Cancer letters.

[25]  Y. M. Lee,et al.  Decursin and decursinol angelate inhibit VEGF-induced angiogenesis via suppression of the VEGFR-2-signaling pathway. , 2009, Carcinogenesis.

[26]  G. Soma,et al.  ROS and innate immunity. , 2009, Anticancer research.

[27]  C. Cahill,et al.  Interleukin (IL) 1β Induction of IL-6 Is Mediated by a Novel Phosphatidylinositol 3-Kinase-dependent AKT/IκB Kinase α Pathway Targeting Activator Protein-1* , 2008, Journal of Biological Chemistry.

[28]  R. Medzhitov.  Origin and physiological roles of inflammation , 2008, Nature.

[29]  N. Jana.  NSAIDs and apoptosis , 2008, Cellular and Molecular Life Sciences.

[30]  Ji-Yeon Kim,et al.  Inhibition of LPS-induced iNOS, COX-2 and cytokines expression by poncirin through the NF-kappaB inactivation in RAW 264.7 macrophage cells. , 2007, Biological & pharmaceutical bulletin.

[31]  M. Abdelrahim,et al.  Regulation of vascular endothelial growth factor receptor-1 expression by specificity proteins 1, 3, and 4 in pancreatic cancer cells. , 2007, Cancer research.

[32]  Geert Raes,et al.  Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. , 2006, Immunobiology.

[33]  M. Abdelrahim,et al.  Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. , 2006, Journal of the National Cancer Institute.

[34]  K. Suk,et al.  Decursin Inhibits Induction of Inflammatory Mediators by Blocking Nuclear Factor-κB Activation in Macrophages , 2006, Molecular Pharmacology.

[35]  Ik-Hwan Kim,et al.  Involvement of PKC and ROS in the cytotoxic mechanism of anti-leukemic decursin and its derivatives and their structure-activity relationship in human K562 erythroleukemia and U937 myeloleukemia cells. , 2005, Cancer letters.

[36]  Sankar Ghosh,et al.  Signaling to NF-kappaB. , 2004, Genes & development.

[37]  S. Kang,et al.  Anti-tumor activities of decursinol angelate and decursin fromAngelica gigas , 2003, Archives of pharmacal research.

[38]  D. Mosser,et al.  The many faces of macrophage activation , 2003, Journal of leukocyte biology.

[39]  D. Green,et al.  Regional analysis of p53 mutations in rheumatoid arthritis synovium , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[40]  S. Weitzman,et al.  Chronic inflammation and cancer. , 2002, Oncology.

[41]  E. Chan,et al.  IFN-γ + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38 mapk in a mouse macrophage cell line , 2001 .

[42]  N. Mackman,et al.  LPS induction of gene expression in human monocytes. , 2001, Cellular signalling.

[43]  H. Adami,et al.  Infections as a major preventable cause of human cancer , 2000, Journal of internal medicine.

[44]  H. Maeda,et al.  Nitric oxide and oxygen radicals in infection, inflammation, and cancer. , 1998, Biochemistry. Biokhimiia.

[45]  M. Blaser,et al.  Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer, and duodenal ulcer risk. , 1995, Cancer research.

[46]  F. Beuvon,et al.  Anti-colony-stimulating factor-1 antibody staining in primary breast adenocarcinomas correlates with marked inflammatory cell infiltrates and prognosis. , 1994, Journal of the National Cancer Institute.

[47]  A. Jemal,et al.  Cancer statistics, 2017 , 2017, CA: a cancer journal for clinicians.

[48]  E. Eruslanov,et al.  Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer. , 2012, American journal of translational research.

[49]  B. Dahal,et al.  Inflammation, immunological reaction and role of infection in pulmonary hypertension. , 2011, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[50]  R. Medzhitov,et al.  Toll-like receptors and cancer , 2009, Nature Reviews Cancer.

[51]  H. Groen,et al.  Non-steroidal anti-inflammatory drugs to potentiate chemotherapy effects: from lab to clinic. , 2007, Critical reviews in oncology/hematology.

[52]  A. Zlotnik.  Involvement of chemokine receptors in organ-specific metastasis. , 2006, Contributions to microbiology.

[53]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.