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TNF- Drives Human CD14⁺ Monocytes to Differentiate into CD70⁺ Dendritic Cells Evoking Th1 and Th17 Responses

Sanju Iwamoto^1,*, Shin-ichi Iwai, Kazuko Tsujiyama, Chika Kurahashi, Kumiko Takeshita, Michio Naoe, Atsuko Masunaga, Yoshio Ogawa, Katsuji Oguchi and Akira Miyazaki^*

^* Department of Biochemistry, Department of Pharmacology, and Department of Urology, School of Medicine, Showa University, Tokyo, Japan; and Department of Surgical Pathology, Showa University Fujigaoka Hospital, Yokohama, Japan

Many mechanisms involving TNF-, 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- 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- 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-, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (M). 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- and TNF-, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF- added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the M (CD14^highCD70⁺CD83^–HLA-DR^–) produced large amounts of MMP-9 and TNF- 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. Therefore, additional stimulation of monocytes with TNF- may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated M-mediated innate immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Sanju Iwamoto, Department of Biochemistry, School of Medicine, Showa University, Hatanodai 1-5-8, Shinagawa-ku, Tokyo, Japan. E-mail address: iwasanju{at}med.showa-u.ac.jp

² Abbreviations used in this paper: RA, rheumatoid arthritis; DC, dendritic cell; M, macrophage; MMP, matrix metalloproteinase; sTNFRI, soluble type I TNF receptor; KLH, keyhole limpet hemocyanin.

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