title: Different mitogen-activated protein kinase-dependent cytokine responses in cells of the monocyte lineage.
abstract: Macrophages release cytokines that may contribute to the chronic inflammation observed in pulmonary conditions such as asthma and chronic obstructive pulmonary disease. Thus, inhibition of macrophage cytokine production may have a therapeutic benefit. Human lung macrophages are a rich source of the proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, and IL-8, that are elevated in the bronchoalveolar lavage and sputum of subjects with respiratory diseases. Cytokine production from both monocytes and macrophages is mediated by mitogen-activated protein kinase (MAPK) pathways. This study compared the effects of a novel p38 MAPK inhibitor, N-cyano-N'-(2-{[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}ethyl)-guanidine (PCG), and an extracellular signal-regulated kinase (ERK) pathway inhibitor, 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD098059), on cytokine release from lipopolysaccharide (LPS)-stimulated human monocytes, monocyte-derived macrophages (MDM), and lung macrophages. Lung macrophages, MDM, and monocytes were stimulated with LPS, and cytokine release was measured by enzyme-linked immunosorbent assay. Immunoblots were performed to confirm p38 and ERK1/2 MAPK expression and activity. PCG inhibited TNF-alpha release more effectively from monocytes compared with MDM or macrophages (maximal inhibition was 99.3 +/- 1.4, 62.7 +/- 4.3, and 58.6 +/- 6.6%, respectively; n = 7-9). PD098059 was less effective at suppressing TNF-alpha release from monocytes compared with MDM and lung macrophages (maximal inhibition was 37.4 +/- 2.8, 70.1 +/- 4.5, and 68.7 +/- 5.1%, respectively; n = 7-9). The pattern of GM-CSF, IL-6, and IL-8 release was comparable with that of TNF-alpha. These data suggest a differential involvement for each of these MAPK pathways in macrophage cytokine production compared with monocytes.
authors.affiliation: Airway Disease Section, Guy Scadding Building, National Heart and Lung Institute, Imperial College London, Dovehouse St., London SW3 6LY, UK. l.donnelly@imperial.ac.uk
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Tudhope
authors.forename: Tricia K
authors.initials: TK
authors.lastname: Finney-Hayward
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Mayer
authors.forename: Mary S
authors.initials: MS
authors.lastname: Barnette
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: Louise E
authors.initials: LE
authors.lastname: Donnelly
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000166:cytology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D016207:Cytokines; D005419:Flavonoids; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one