Alternatively activated alveolar macrophages in pulmonary fibrosis—mediator production and intracellular signal transduction

• Published in: Clinical immunology (Orlando, Fla.) Vol. 137; no. 1; pp. 89 - 101
• Main Authors: Pechkovsky, Dmitri V, Prasse, Antje, Kollert, Florian, Engel, Kathrin M.Y, Dentler, Jan, Luttmann, Werner, Friedrich, Karlheinz, Müller-Quernheim, Joachim, Zissel, Gernot
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 01.10.2010; Elsevier
• Subjects: Adult; Aged; Aged, 80 and over; Allergy and Immunology; Alveolar macrophages; Alveoli; Biological and medical sciences; Bronchoalveolar Lavage Fluid - cytology; CCL17; CCL18; CCL22; Chemokines, CC - genetics; Chemokines, CC - metabolism; Cytokines - metabolism; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression - drug effects; Humans; Idiopathic Pulmonary Fibrosis - immunology; Idiopathic Pulmonary Fibrosis - metabolism; IL-1RA; Interleukin 1 Receptor Antagonist Protein - genetics; Interleukin 1 Receptor Antagonist Protein - metabolism; Interleukin-10 - pharmacology; Interleukin-4 - pharmacology; Interleukin-8 - metabolism; JAK/STAT pathway; Lectins, C-Type - metabolism; M2 phenotype; Macrophage Activation - drug effects; Macrophage Activation - immunology; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Male; Mannose-Binding Lectins - metabolism; Medical sciences; Middle Aged; Monocytes - drug effects; Monocytes - immunology; Monocytes - metabolism; Pneumology; Pulmonary fibrosis; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - immunology; Pulmonary Fibrosis - metabolism; Receptors, Cell Surface - metabolism; Respiratory system : syndromes and miscellaneous diseases; Sarcoidosis; Sarcoidosis, Pulmonary - complications; Sarcoidosis, Pulmonary - diagnosis; Sarcoidosis, Pulmonary - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Scleroderma, Systemic - complications; Scleroderma, Systemic - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; STAT Transcription Factors - metabolism; Th2 cytokines; Tumor Necrosis Factor-alpha - metabolism; Young Adult; SSc; M2 phenotype; M2; SAR; JAK/STAT pathway; alveolar macrophages; signal transducer and activator of transcription; Th2 cytokines; systemic sclerosis; alternatively activated macrophages; TGF-β; interleukin; CCL18; CCL17; IL; IL-1RA; CCL22; sarcoidosis; idiopathic pulmonary fibrosis; AM; BAL; CCL; STAT; Pulmonary fibrosis; transforming growth factor-β; bronchoalveolar lavage; CC-chemokine ligand; IPF; Sarcoidosis; Alveolar macrophages; Biosynthesis; Signal transduction; Immunology; Systemic disease; T-Lymphocyte; Th2 lymphocyte; Jak protein tyrosine kinase; Lung disease; Respiratory disease; Interleukin 1 receptor antagonist; Cytokine; Phenotype; Transduction factor STAT; Intracellular; Macrophage
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2010.06.017

Abstract Activated macrophages have been characterized as M1 and M2 according to their inflammatory response pattern. Here we analyzed the M2 marker expression and intracellular signal transduction in the course of cytokine-driven differentiation. We found elevated spontaneous production of the chemokines CCL17, CCL18 and CCL22 and increased expression of CD206 by alveolar macrophages from patients with lung fibrosis. Stimulation of normal human AM with Th2 cytokines IL-4 and/or IL-10 in vitro revealed IL-4 as the most powerful inducer of M2-phenotype in AM and monocytes. Importantly, IL-10 enhanced IL-4-induced expression of CCL18 and IL-1RA in a synergistic fashion. IL-4/IL-10 stimulation induces a strong activation of STAT3 in AM from fibrosis patients. These results suggest an important role for M2 polarized AM in the pathogenesis of pulmonary fibrosis and indicate that both IL-4 and IL-10 account for human AM phenotype shift to M2, as seen in patients with fibrotic interstitial lung diseases.