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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Different Mitogen-Activated Protein Kinase-Dependent Cytokine Responses in Cells of the Monocyte Lineage

Airway Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom (S.J.T., T.K.F-H., P.J.B., L.E.D.); Department of Histopathology, Royal Brompton Hospital, London, United Kingdom (A.G.N.); and Respiratory and Inflammation CEDD, GlaxoSmithKline, King of Prussia, Philadelphia, Pennsylvania (R.J.M., M.S.B.)

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)-, 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- 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- 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-. These data suggest a differential involvement for each of these MAPK pathways in macrophage cytokine production compared with monocytes.

Address correspondence to: Dr. Louise E. Donnelly, Airway Disease Section, Guy Scadding Building, National Heart and Lung Institute, Imperial College London, Dovehouse St., London SW3 6LY, UK. E-mail: l.donnelly{at}imperial.ac.uk

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