title: Impact of p38 mitogen-activated protein kinase inhibition on immunostimulatory properties of human 6-sulfo LacNAc dendritic cells.
abstract: p38 Mitogen-activated protein kinase (MAPK) plays a crucial role in the induction and regulation of innate and adaptive immunity. Furthermore, p38 MAPK can promote tumor invasion, metastasis, and angiogenesis. Based on these properties, p38 MAPK inhibitors emerged as interesting candidates for the treatment of immune-mediated disorders and cancer. However, the majority of p38 MAPK inhibitor-based clinical trials failed due to poor efficacy or toxicity. Further studies investigating the influence of p38 MAPK inhibitors on immunomodulatory capabilities of human immune cells may improve their therapeutic potential. Here, we explored the impact of the p38 MAPK inhibitor SB203580 on the pro-inflammatory properties of native human 6-sulfo LacNAc dendritic cells (slanDCs). SB203580 did not modulate maturation of slanDCs and their capacity to promote T-cell proliferation. However, SB203580 significantly reduced the production of pro-inflammatory cytokines by activated slanDCs. Moreover, inhibition of p38 MAPK impaired the ability of slanDCs to differentiate naïve CD4(+) T cells into T helper 1 cells and to stimulate interferon-γ secretion by natural killer cells. These results provide evidence that SB203580 significantly inhibits various important immunostimulatory properties of slanDCs. This may have implications for the design of p38 MAPK inhibitor-based treatment strategies for immune-mediated disorders and cancer.
authors.affiliation: Institute of Immunology, Medical Faculty, TU Dresden, Dresden, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Langosch
authors.affiliation: Institute of Immunology, Medical Faculty, TU Dresden, Dresden, Germany.
authors.forename: Rebekka
authors.initials: R
authors.lastname: Wehner
authors.affiliation: Host-Tumor-Interactions Group, Academic Unit of Clinical Oncology, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Ania
authors.initials: A
authors.lastname: Malecka
authors.affiliation: Host-Tumor-Interactions Group, Academic Unit of Clinical Oncology, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Hester A
authors.initials: HA
authors.lastname: Franks
authors.affiliation: Department of Dermatology, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Schäkel
authors.affiliation: Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bachmann
authors.affiliation: Host-Tumor-Interactions Group, Academic Unit of Clinical Oncology, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Jackson
authors.affiliation: Institute of Immunology, Medical Faculty, TU Dresden, Dresden, Germany; Center for Regenerative Therapies Dresden, Dresden, Germany. Electronic address: marc.schmitz@tu-dresden.de.
authors.forename: Marc
authors.initials: M
authors.lastname: Schmitz
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002450:Cell Communication; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D056747:Immunomodulation / Q000187:drug effects*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D061251:Primary Cell Culture; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Dendritic cells; Immune-mediated disorders; T cells; Tumor immunology; p38 Mitogen-activated protein kinase