Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transduction.
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.
Pechkovsky
Dmitri V
DV
Department of Pneumology, Medical Center, Albert-Ludwigs University, Freiburg, Germany.
Prasse
Antje
A
Kollert
Florian
F
Engel
Kathrin M Y
KM
Dentler
Jan
J
Luttmann
Werner
W
Friedrich
Karlheinz
K
Müller-Quernheim
Joachim
J
Zissel
Gernot
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D017565:Sarcoidosis, Pulmonary / Q000150:complications / Q000175:diagnosis / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000150:complications / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
D019742:Chemokines, CC; D016207:Cytokines; C508609:IL10 protein, human; C508598:IL4 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D016209:Interleukin-8; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011956:Receptors, Cell Surface; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4