Tumor necrosis factor-alpha- and interleukin-6-triggered mast cell development from mouse spleen cells

We previously showed that interleukin-3 (IL-3) alone is not sufficient, although it is essential for murine mucosal-type mast cell development and that prostaglandin E (PGE) and interferon-gamma (IFN-gamma) are critical for survival or differentiation of mast cell precursors. We also confirmed that IL-4 is a key inhibitor for mast cell precursors despite being a growth factor of mast cells. In the present work, mouse spleen cells were cultured with recombinant (r) IL-1 beta, rIL-5, rIL-6, rIL-9, granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor (SCF), tumor transforming growth factor-beta (TGF-beta), or tumor necrosis factor-alpha (TNF-alpha) in the presence of endogenous IL-3. After 12 days of culture. mast cell development was induced by rIL-6 and rTNF-alpha. rIL-1 beta, rIL-5, rGM-CSF, rTGF-beta and even the mast cell growth factors, rIL-9 and rSCF, failed to induce mast cell development. However, unlike IL-9 and SCF, IL-6 and TNF-alpha did not promote the growth of mast cells already developed. Macrophage may be one of the responsive cells of IL-6 and TNF-alpha in the cultures, because removal of macrophages greater reduced the mast cell development induced by the cytokines. The actions of TNF-alpha and IL-6 were inhibited by indomethacin, an inhibitor for prostaglandin synthesis, and by neutralizing anti-IFN-gamma and anti-IL-3 antibodies. rIL-4, when added at the start of the culture, also inhibited mast cell development induced by rIL-6 and rTNF-alpha. Nevertheless, neutralizing anti-IL-6 and anti-TNF-alpha antibodies did not suppress mast cell development induced by PGE and IFN-gamma. TNF-alpha and IL-6 enhanced IFN-gamma production, but suppressed IL-4 production in the cultures. Mast cell numbers induced were inversely and directly proportional to IL-4 and IFN-gamma levels, respectively. These results indicate that inflammatory mediators as triggers are important for mast cell development, although they are not the mast cell growth factors. (C) 1997 by The American Society of Hematology.