Insulin and insulin-like growth factor-1 promote mast cell survival via activation of the phosphatidylinositol-3-kinase pathway.
OBJECTIVE
Mast cells (MCs) play central roles for the onset and development of immediate-type and inflammatory allergic reactions. Since the inverse relationship between atopic disorders and diabetes mellitus has been observed in animals and humans, we investigated the effects of insulin (Ins) on MC signaling and biological function.


METHODS
In bone marrow-derived MCs (BMMCs) from wild-type as well as SHIP-deficient mice Ins as well as insulin-like growth factor-1 (IGF-I)-triggered intracellular signaling events and MC effector functions were studied.


RESULTS
We found that the addition of either Ins or IGF-1 to BMMCs triggers the phosphorylation of protein kinase B (PKB) and p38 kinase but not extracellular signal-regulated kinase (Erk). We also found that Ins/IGF-1 stimulates the tyrosine phosphorylation of SHIP1 and, in keeping with this, Ins/IGF-1-induced PKB phosphorylation is higher in SHIP1-/- BMMCs and is inhibited in SHIP+/+ as well as SHIP1-/- BMMCs with inhibitors of phosphatidylinositol-3-kinase (PI3K). Ins/IGF-1, like antigen (Ag), also stimulates the Rac-dependent activation of PAK as well as the production of hydrogen peroxide (H2O2). To elucidate the role of Ins and IGF-1 in MC biology, we studied their effects on Ag-mediated degranulation and MC survival. Although both only slightly enhanced Ag-mediated degranulation, they significantly promoted MC survival in the absence of IL-3 in a PI3K-dependent manner.


CONCLUSIONS
The promotion of BMMC survival by induction of Ins/IGF-1 signaling may, in part, be responsible for the inverse correlation observed between atopic disorders and diabetes mellitus.
Lessmann
Eva
E
Department of Molecular Immunology, Biology III, University of Freiburg and Max-Planck-Institute for Immunobiology, Freiburg, Germany.
Grochowy
Gordon
G
Weingarten
Lars
L
Giesemann
Torsten
T
Aktories
Klaus
K
Leitges
Michael
M
Krystal
Gerald
G
Huber
Michael
M
D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases