Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen

Negative Signaling in Fc Receptor Complexes

“…An exposure of mast cells to IgE in the absence of antigen was indeed reported 1) to up-regulate the expression of membrane FcεRI (Hsu and MacGlashan, 1996;MacGlashan et al, 1997), 2) to increase the survival of mast cells in the absence of growth factors (Asai et al, 2001;Kawakami and Galli, 2002), and 3) to induce cytokine secretion (Kalesnikoff et al, 2001;Pandey et al, 2004;Kohno et al, 2005). The effect of monomeric IgE on mast cell survival and cytokine secretion was found to depend on the FcRγ ITAM (Kohno et al, 2005), but not the up-regulation of FcεRI expression. The effect on receptor expression was shown to result from slowing down the removal of FcεRI from the membrane and its subsequent degradation without affecting the rate of FcεRI synthesis (Borkowski et al, 2001).…”

“…Interestingly, however, quantitative variations of receptor aggregation were found to result in qualitative variation in cellular responses. A low level of FcεRI aggregation, induced by incubating mast cells with IgE in the absence of (known) antigen, triggered intracellular signals leading to the secretion of IL-3 or MCP-1, but not to degranulation, whereas a high level of receptor aggregation, induced by incubating with multivalent antigen mast cells sensitized with the same IgE, triggered both degranulation and cytokine secretion (Gonzalez-Espinosa et al, 2003;Yamasaki et al, 2004;Kohno et al, 2005). Molecular mechanisms that enable quantitative differences in receptor aggregation to produce qualitatively different responses remain to be elucidated.…”

Regulation of allergy by Fc receptors

“…These responses were all induced by high concentrations (several µg/ml) of monoclonal IgE anti-DNP/TNP, among which highly and poorly "cytokinergic" IgE were distinguished [17]. Mast cell survival and cytokine secretion were found to depend on the FcRγ ITAM [16] and FcεRI internalization required the src kinase Lyn, whereas degranulation, cytokine secretion and survival required also Syk [18]. It thus became thought that the binding of some IgE to FcεRI could trigger intracellular signals similar to those triggered by FcεRI aggregation.…”

“…Recently, however, IgE was reported to increase the survival of mouse mast cells in the absence of IL-3 [13,14] and to induce FcεRI internalization, cytokine secretion and degranulation [15,16]. These responses were all induced by high concentrations (several µg/ml) of monoclonal IgE anti-DNP/TNP, among which highly and poorly "cytokinergic" IgE were distinguished [17].…”

“…Low levels of FcεRI aggregation, induced by IgE alone, triggered the secretion of IL-3 or MCP-1, but not degranulation, whereas high levels of receptor aggregation, induced by the same IgE and multivalent antigen, triggered both degranulation and cytokine secretion [16,20,21]. Using FcRγ-deficient mast cells that expressed CD8/FcRγ chimeras and were challenged with anti-CD8 antibodies, it was found that degranulation required stronger stimulation whereas survival required longer stimulations [21].…”