Mebendazole-induced M1 polarisation of THP-1 macrophages may involve DYRK1B inhibition

• Published in: BMC research notes 2019-04, Vol.12 (1), p.234-7, Article 234
• Main Authors: Blom, Kristin, Rubin, Jenny, Berglund, Malin, Jarvius, Malin, Lenhammar, Lena, Parrow, Vendela, Andersson, Claes, Loskog, Angelica, Fryknäs, Mårten, Nygren, Peter, Larsson, Rolf
• Format: Article
• Language: English
• Subjects: Antigens, CD - genetics; Antigens, CD - immunology; Antigens, Differentiation, Myelomonocytic - genetics; Antigens, Differentiation, Myelomonocytic - immunology; Antinematodal Agents - metabolism; Antinematodal Agents - pharmacology; Antiparasitic agents; Cancer; Cancer research; Cancer treatment; CD163 antigen; CD80 antigen; Cell culture; Cell cycle; Cell Differentiation - drug effects; Cytokines; Dendritic cells; Dyrk Kinases; DYRK1B; Extracellular signal-regulated kinase; Gene Expression Regulation; Health aspects; Heterocyclic Compounds, 2-Ring - pharmacology; Humans; Immune response; Immunotherapy; Inflammation; Interferon-gamma - genetics; Interferon-gamma - immunology; Interferon-gamma - pharmacology; Interleukins - genetics; Interleukins - immunology; Kinases; Lipopolysaccharides; Lipopolysaccharides - pharmacology; M1 polarisation; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - immunology; Mebendazole; Mebendazole - metabolism; Mebendazole - pharmacology; Monocytes; Monocytes and macrophages; Phenols (Class of compounds); Phenotypes; Phosphorylation; Phosphorylation - drug effects; Physiological aspects; Protein Binding; Protein Kinase Inhibitors - pharmacology; Protein kinases; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - immunology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - immunology; Proteins; Proto-Oncogene Proteins c-abl - genetics; Proto-Oncogene Proteins c-abl - immunology; Pyrimidines - pharmacology; Receptors, Cell Surface - genetics; Receptors, Cell Surface - immunology; Research Note; Signal Transduction; Software; Statistical analysis; Testing; Tetradecanoylphorbol Acetate - pharmacology; THP-1 Cells; Tyrosine; γ-Interferon
• ISSN: 1756-0500; 1756-0500
• DOI: 10.1186/s13104-019-4273-5

We recently showed that the anti-helminthic compound mebendazole (MBZ) has immunomodulating activity by inducing a M2 to M1 phenotype switch in monocyte/macrophage models. In the present study we investigated the potential role of protein kinases in mediating this effect. MBZ potently binds and inhibits Dual specificity tyrosine-phosphorylation-regulated kinase 1B (DYRK1B) with a Kd and an IC of 7 and 360 nM, respectively. The specific DYRK1B inhibitor AZ191 did not mimic the cytokine release profile of MBZ in untreated THP-1 monocytes. However, in THP-1 cells differentiated into macrophages, AZ191 strongly induced a pro-inflammatory cytokine release pattern similar to MBZ and LPS/IFNγ. Furthermore, like MBZ, AZ191 increased the expression of the M1 marker CD80 and decreased the M2 marker CD163 in THP-1 macrophages. In this model, AZ191 also increased phospho-ERK activity although to a lesser extent compared to MBZ. Taken together, the results demonstrate that DYRK1B inhibition could, at least partly, recapitulate immune responses induced by MBZ. Hence, DYRK1B inhibition induced by MBZ may be part of the mechanism of action to switch M2 to M1 macrophages.