title: OK-432-stimulated chemokine secretion from human monocytes depends on MEK1/2, and involves p38 MAPK and NF-κB phosphorylation, in vitro.
abstract: Interaction between the immune system and cancer cells allows for the use of biological response modifiers, like OK-432, in cancer therapy. We have studied the involvement of monocytes (MOs) in the immune response to OK-432 by examining MCP-1, MIP-1α and MIP-1β secretion, in vitro. OK-432-induced IL-6/TNF-α secretion has previously been shown to depend on mitogen-activated protein kinases (MAPKs) ERK1/2 and p38, and we therefore investigated the role of these MAPKs in OK-432-induced chemokine secretion. Here we demonstrate that pharmacological MEK1/2 kinase inhibition generally impaired chemokine secretion from MOs, whereas p38 MAPK inhibition in particular reduced MIP-1α production. Furthermore, simultaneous inhibition of MEK1/2 and Syk kinase was seen to have an additive impact on reduced MCP-1, MIP-1α and MIP-1β secretion. Based on single cell flow cytometry analyses, OK-432, lipoteichoic acid (LTA) and lipopolysaccharide (LPS) were seen to induce p38 MAPK and NF-κB phosphorylation in MOs with different time kinetics. LTA and LPS have been shown to induce ERK1/2 phosphorylation, whereas the levels of phosphorylated ERK1/2 remained constant following OK-432 treatment at the time points tested. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns, and we demonstrate increased TLR2 cell surface levels on the MO population, most profoundly following stimulation with LTA and OK-432. Together these results indicate that modulation of MEK1/2 and p38 MAPK signalling could affect the response to OK-432 treatment, having the potential to improve its therapeutic potential within cancer and lymphangioma treatment.
authors.affiliation: Department of Surgical Sciences, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: Carla
authors.initials: C
authors.lastname: Olsnes
authors.forename: Therese
authors.initials: T
authors.lastname: Bredholt
authors.forename: Jan
authors.initials: J
authors.lastname: Olofsson
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Aarstad
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D018925:Chemokines / Q000378:metabolism*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010844:Picibanil / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D000072377:Syk Kinase; D013682:Teichoic Acids / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002070:Butadienes; D018925:Chemokines; D007155:Immunologic Factors; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009570:Nitriles; D013682:Teichoic Acids; C113580:U 0126; D010844:Picibanil; C009900:lipoteichoic acid; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human