Truncated thioredoxin (Trx80) induces differentiation of human CD14+ monocytes into a novel cell type (TAMs) via activation of the MAP kinases p38, ERK, and JNK.
Thioredoxin truncated at its carboxy terminal (Trx80) acts as a cytokine that stimulates monocytes and eosinophils. In the present study, Trx80 was shown to induce differentiation of human CD14(+) monocytes into a cell type not described previously, which we designate as Trx80-activated monocytes (TAMs). TAMs resemble immature dendritic cells (iDCs) generated in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) in that both these cell populations exhibit increased proportions of CD1a(+) and mannose receptor (MR)(+) cells. However, in contrast to iDCs, TAMs express high proportion of CD14 and lower proportion of CD83 and HLA-DR. Functional assays revealed that, in comparison to iDCs, TAMs 1) exhibit a higher pinocytic capacity; 2) release significantly higher amounts of the proinflammatory cytokines tumor necrosis factor-alpha (TNF alpha), IL-1 beta, and IL-6 and of the anti-inflammatory cytokine IL-10; and 3) induce a significantly lower proliferative response in allogeneic peripheral blood mononuclear cells (PBMCs). Indeed, Trx80 appears to be the first endogenous substance shown to have the capacity on its own to induce IL-10 production by monocytes. Analysis of the mitogen-activated protein (MAP) kinase signaling pathway revealed that Trx80 induces phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). We propose that Trx80 is an early signal in response to danger, and that TAMs may play a major role in triggering innate immune responses.
Pekkari
Klas
K
Medical Nobel Institute for Biochemistry, Department of Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
Goodarzi
Mohammad Taghi
MT
Scheynius
Annika
A
Holmgren
Arne
A
Avila-Cariño
Javier
J
D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003911:Dextrans / Q000378:metabolism; D004705:Endocytosis / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis*; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013879:Thioredoxins / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology
D016207:Cytokines; D003911:Dextrans; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D010446:Peptide Fragments; D011994:Recombinant Proteins; C427943:Trx80 protein, human; D013879:Thioredoxins; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D016650:Fluorescein-5-isothiocyanate