title: Inhibition of p38 MAP kinase during cellular activation results in IFN-gamma-dependent augmentation of IL-12 production by human monocytes/macrophages.
abstract: Interleukin-12 (IL-12) is a key immunomodulatory cytokine produced by antigen-presenting cells that promotes cellular immunity and enables the generation of protective immunity against intracellular pathogens and tumours. Therefore, modulation of IL-12 activity is a primary immunotherapeutic goal. However, little is known about its regulation. Signalling via p38 MAPK has been implicated in the control of inflammatory responses and is therefore a potential therapeutic target. We have used the highly selective p38 MAPK inhibitor (SB203580) to examine the effect of this pathway on the production of IL-12. Surprisingly, we found that SB203580 strongly up-regulated LPS induced IL-12p40 at the protein (intracellular and secreted) and mRNA levels in PBMC cultures. The effect on IL-12 was apparent using both T cell-independent and T cell-dependent stimuli but not in unstimulated cultures, indicating that activation signals are required. Furthermore, the production of IFN-gamma by T cells is crucial as production was not increased in LPS-stimulated, purified adherent monocytes/macrophages without the addition of exogenous IFN-gamma. These results provide evidence that p38 MAPK has an unexpected suppressive effect on IL-12p40 gene transcription, and suggests interplay between p38 MAPK- and IFN-gamma -mediated signals in the regulation of IL-12 production by monocytes/macrophages. Furthermore, the importance of IL-12 as a key immunoregulatory cytokine suggests that the clinical application of pyrinidyl imidazole inhibitors, such as SB203580, may need to be reassessed.
authors.affiliation: Division of Oncology, Department of OGEM, St George's Hospital Medical School, London, UK. jmarriot@sghms.ac.uk
authors.forename: J B
authors.initials: JB
authors.lastname: Marriott
authors.forename: I A
authors.initials: IA
authors.lastname: Clarke
authors.forename: A G
authors.initials: AG
authors.lastname: Dalgleish
mesh_terms: D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000096:biosynthesis; D023201:CD40 Ligand / Q000096:biosynthesis; D002448:Cell Adhesion; D002478:Cells, Cultured; D018920:Coculture Techniques; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008934:Mitogens / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D019013:CD40 Antigens; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D008934:Mitogens; D010835:Phytohemagglutinins; D011725:Pyridines; D012333:RNA, Messenger; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580