Rapid and large amount of autocrine IL-3 production is responsible for mast cell survival by IgE in the absence of antigen.
Cross-linking FcepsilonRI on mast cells by immunoglobulin E (IgE) and antigen (Ag) initiates cascades leading to antiparasitic or allergic responses. It was recently reported that IgE without antigen, IgE(-Ag), actively promotes mast cell survival. Although we have demonstrated that the immunoreceptor tyrosine-based activation motif within FcRgamma is essential for IgE(-Ag)-induced mast cell survival, the underlying mechanism remains still unclear. Here, we investigated the mechanism of IgE(-Ag)-induced survival using mast cells lacking several downstream molecules. Lyn and Syk were essential, whereas Fyn, Gab2, and the phosphoinositide 3-kinase-Akt pathway were not critical for survival. Failure of survival in FcRgamma-/- bone marrow mast cells (BMMCs) was rescued by coculture with IgE-treated wild-type BMMCs, suggesting that survival is induced not directly through FcepsilonRI signals. We found that the survival is predominantly mediated by high production of interleukin 3 (IL-3), evidenced by severe impairment of survival by anti-IL-3 and in IL-3-/- BMMCs. The up-regulation of Bcl-xL/Bcl-2 by IgE was abrogated in IL-3-/- BMMCs, whereas the expression of histidine decarboxylase was normally induced. These results indicate that IL-3 plays a crucial role for IgE(-Ag)-induced mast cell survival, functioning in an autocrine manner by inducing the Bcl-xL/Bcl-2 via signal transducer and activator of transduction 5. We further suggest that IgE(-Ag)-mediated gene expression in mast cells is regulated at least 2 mechanisms: autocrine IL-3 dependent and independent.
Kohno
Masayuki
M
Department of Molecular Genetics, Graduate School of Medicine, Chiba University, Chiba, Japan.
Yamasaki
Sho
S
Tybulewicz
Victor L J
VL
Saito
Takashi
T
D000818:Animals; D000941:Antigens; D019898:Autocrine Communication; D001854:Bone Marrow Cells; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism; D004792:Enzyme Precursors / Q000378:metabolism; D007073:Immunoglobulin E / Q000502:physiology*; D007377:Interleukin-3 / Q000096:biosynthesis* / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D000072377:Syk Kinase; D015534:Trans-Activators / Q000378:metabolism; D051020:bcl-X Protein; D019061:src-Family Kinases / Q000378:metabolism
D000941:Antigens; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D007377:Interleukin-3; D047908:Intracellular Signaling Peptides and Proteins; D008894:Milk Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017452:Receptors, IgG; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D051020:bcl-X Protein; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases