Macrophages: the macrophage response following phagocytosis of apoptotic cells

Emeritus professor of TOHO UNIVERSITY.

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What is apoptosis? Difference between apoptotic cells and live cells Our research (1) Our research (2) Our research (3)

Our research (2) immature dendritic cells and dead cells

Mature dendritic cells are potent antigen presenting cells and play an important role in immune response,

On the other hand, immature dendritic cells can phagocytose apoptotic cells less efficiently than macrophages.  

MT decided to explore cytokines specifically produced by immature dendritic cells upon coculturing with late apoptotic cells, which are otherwise called as secondary necrotic cells.  He identified IL-6 and IL-12p40 as such cytokines which were produced at the levels of mRNA and protein.  They were not produced upon coculturing with necrotic cells, which were obtained after one cycle of freeze and thawing.  IL-6 was produced more significantly than IL-12p40, and was found to prevent immature dendritic cells from spontaneous maturation (Cell Immunol 226, 105-15, 2003; 228, 138, 2004).  Phagocytosis of apoptotic cells also prevents immature dendritic cells from LPS-induced maturation.  These mechanisms may be responsible for keeping unresponsiveness toward apoptotic cells

Since immature dendritic cells are often seen in the close proximity with macrophages (J. Exp. Med. 183, 1865-78, 1996; Int Rev Cytol 197, 83-136, 2000), MT examined the effect of immature dendritic cells on MIP-2 production after coculturing of thioglycollate broth-induced peritoneal macrophages with late apoptotic cells, which are otherwise called as secondary necrotic cells.  He found that immature dendritic cells suppress MIP-2 production and that the suppression is not seen when immature dendritic cells are separated from macrophages with a Trans well, as shown in the figure below (red square; [DC+Apo]).  Consequently immature dendritic cells appear to suppress MIP-2 production by macrophages in a contact-dependent manner.  This was true with Kupffer cells and other late apoptotic cells.  

Although it was hypothesized that apoptotic cell clearance is competitively inhibited by each other, immature dendritic cells rather enhanced phagocytosis of apoptotic cells by macrophages.  Moreover antibodies against TGF-β and IL-10 cancelled suppression.  Since these cytokines were not detected at the protein level in the supernatants, they were detected at the mRNA levels with RT-PCR as shown in the figure below.  

Upon three cell coculture, TGF-β and IL-10 production was enhanced in immature dendritic cells.  These findings provide another mechanism to prevent the macrophage response following phagocytosis of apoptotic cells (J. Leukoc Biol. 75, 865-73, 2004).  Based on these contributions to science, MT received a Ph. D. degree in March, 2004.  



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