TNF-alpha drives human CD14+ monocytes to differentiate into CD70+ dendritic cells evoking Th1 and Th17 responses.
Many mechanisms involving TNF-alpha, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-alpha to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14(+) monocytes cultured in the presence of TNF-alpha and GM-CSF converted to CD14(+) CD1a(low) adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-alpha, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (M phi). The mature DC (CD83(+) CD70(+) HLA-DR (high) CD14(low)) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-gamma and TNF-alpha, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-alpha added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the M phi (CD14(high)CD70(+)CD83(-)HLA-DR(-)) produced large amounts of MMP-9 and TNF-alpha without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated M phi. Therefore, additional stimulation of monocytes with TNF-alpha may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated M phi-mediated innate immunity.
Iwamoto
Sanju
S
Department of Biochemistry, School of Medicine, Showa University, Tokyo, Japan. iwasanju@med.showa-u.ac.jp
Iwai
Shin-ichi
S
Tsujiyama
Kazuko
K
Kurahashi
Chika
C
Takeshita
Kumiko
K
Naoe
Michio
M
Masunaga
Atsuko
A
Ogawa
Yoshio
Y
Oguchi
Katsuji
K
Miyazaki
Akira
A
D053282:CD27 Ligand / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D020381:Interleukin-17 / Q000096:biosynthesis*; D053759:Interleukin-23 / Q000502:physiology; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018448:Models, Immunological; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D053282:CD27 Ligand; D018836:Inflammation Mediators; D020381:Interleukin-17; D053759:Interleukin-23; D018950:Lipopolysaccharide Receptors; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor