Insulin and insulin-like growth factor-1 promote mast cell survival via activation of the phosphatidylinositol-3-kinase pathway

Lessmann, Eva; Grochowy, Gordon; Weingarten, Lars; Giesemann, Torsten; Aktories, Klaus; Leitges, Michael; Krystal, Gerald; Huber, Michael

doi:10.1016/j.exphem.2006.05.022

« Previous Next »Experimental Hematology
Volume 34, Issue 11 , Pages 1532-1541, November 2006

Insulin and insulin-like growth factor-1 promote mast cell survival via activation of the phosphatidylinositol-3-kinase pathway

Eva Lessmann
- Department of Molecular Immunology, Biology III, University of Freiburg and Max-Planck-Institute for Immunobiology, Freiburg, Germany
Gordon Grochowy
- Department of Molecular Immunology, Biology III, University of Freiburg and Max-Planck-Institute for Immunobiology, Freiburg, Germany
Lars Weingarten
- Department of Molecular Immunology, Biology III, University of Freiburg and Max-Planck-Institute for Immunobiology, Freiburg, Germany
Torsten Giesemann
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany
Klaus Aktories
- Institute for Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany
Michael Leitges
- Max Planck Institute for Experimental Endocrinology, Hannover, Germany
Gerald Krystal
- Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Michael Huber
- Department of Molecular Immunology, Biology III, University of Freiburg and Max-Planck-Institute for Immunobiology, Freiburg, Germany
- Offprint requests to: Michael Huber, Ph.D., University Freiburg, Department of Molecular Immunology, Biology III, Stuebeweg 51, Freiburg 79108, Germany

Received 25 October 2005; received in revised form 25 May 2006; accepted 26 May 2006.

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.

Conclusion

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.