Inhibitory effect of IQ-1S, a selective c-Jun N-terminal kinase (JNK) inhibitor, on phenotypical and cytokine-producing characteristics in human macrophages and T-cells

• Published in: European journal of pharmacology Vol. 878; p. 173116
• Main Authors: Seledtsov, Victor I., Malashchenko, Vladimir V., Meniailo, Maksim E., Atochin, Dmitriy N., Seledtsova, Galina V., Schepetkin, Igor A.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05-07-2020
• Subjects: Adult; Anti-inflammatory; Antigens, Differentiation, T-Lymphocyte - drug effects; Blood - metabolism; c-Jun N-Terminal kinase; Cell Differentiation - drug effects; Cytokine; Cytokines - metabolism; Drug Discovery; Female; Humans; Immunotherapy - methods; JNK inhibitor; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; Lipopolysaccharides - metabolism; Lymphocyte Activation - drug effects; Macrophages - drug effects; Male; Monocyte/macrophage; Monocytes - drug effects; Oximes - pharmacology; Peptides - pharmacology; Phenotype; Phenylacetates - pharmacology; Protein Kinase Inhibitors - pharmacology; Quinoxalines - pharmacology; Receptors, Fc - metabolism; Receptors, Interferon - metabolism; T cell; T-Lymphocytes - drug effects; Time Factors; СD expression; Monocyte/macrophage; c-Jun N-Terminal kinase; T cell; Cytokine; СD expression; JNK inhibitor; Anti-inflammatory
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2020.173116

c-Jun N-terminal kinase (JNK) is a critical mitogen activated protein kinase (MAPK) implicated in inflammatory processes, with IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt) being a high-affinity JNK inhibitor with pronounced anti-inflammatory properties. Here, we studied direct effects of IQ-1S on phenotypical and cytokine-producing characteristics of activated human monocytes/macrophages and T cells in vitro. Purified monocyte/macrophage cells were activated by bacterial lipopolysaccharide (LPS, 1 μg/ml) for 24 h, while T cells were activated by particles conjugated with antibodies (Abs) against human CD2, CD3, and CD28 for 48 h. Treatment with IQ-1S (0.5–25 μМ) in the presence of LPS reduced percentages of CD197 (CCR7)-positive cells in macrophage cultures, without affecting CD16+ (FcγRIII, low-affinity Fc-receptor), CD119+ (interferon-γ receptor 1), and CD124+ (IL-4 receptor α-subunit) cells. In addition, IQ-1S reduced production of tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-10 in macrophage cultures. In activated T cell cultures, IQ-1S decreased CD25+ cell numbers in both CD4-positive and CD4-negative T cell compartments. Central memory СD45RA−/СD197+ and effector memory СD45RA−/СD197- T cells were more sensitive to IQ-1S-mediated suppression, as compared to naïve СD45RA+/СD197+ and terminally-differentiated effector СD45RA+/СD197- T cells. IQ-1S also suppressed T-cell cytokine production (IL-2, interferon-ɣ, IL-4, and IL-10). Collectively, the results suggest that both human macrophage and T cells could be immediate cell targets for IQ-1S-based anti-inflammatory immunotherapy. IQ-1S-mediated suppressive effects were unlikely to be associated with macrophage/T helper polariation.
•IQ-1S, a selective c-Jun N-terminal kinase (JNK) inhibitor, suppresses functionality of both macrophages and T cells.•Memory T cells are more sensitive to IQ-1S-mediated suppression, as compared to naïve T cells.•IQ-1S-mediated immunomodulation is not associated with macrophage /T helper polarization.