Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 123, Issue 3, Pages 603-611Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2008.12.004
Keywords
Apoptosis; eosinophils; inflammation; IL-5; phosphatidylinositol-3 kinase; proviral integration site for Moloney murine leukemia virus
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Funding
- Swiss National Science Foundation [310000-107526, 320000-116304]
- OPO Foundation, Zurich, Switzerland
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Background: Eosinophil differentiation, activation, and survival are largely regulated by IL-5. IL-5-mediated transmembrane signal transduction involves both Lyn-mitogen-activated protein kinases and Janus kinase 2-signal transducer and activator of transcription pathways. Objective: We sought to determine whether additional signaling molecules/pathways are critically involved in IL-5-mediated eosinophil survival. Methods: Eosinophil survival and apoptosis were measured in the presence and absence of IL-5 and defined pharmacologic inhibitors in vitro. The specific role of the serine/threonine kinase proviral integration site for Moloney murine leukemia virus (Pim) 1 was tested by using HIV-transactivator of transcription fusion proteins containing wild-type Pim-1 ora dominant-negative form of Pim-1. The expression of Pim-1 in eosinophils was analyzed by means of immunoblotting and immunofluorescence. Results: Although pharmacologic inhibition of phosphatidylinositol-3 kinase (PI3K) by LY294002, wortmannin, or the selective PI3K p110 delta isoform inhibitor IC87114 was successful in each case, only LY294002 blocked increased IL-5-mediated eosinophil survival. This suggested that LY294002 inhibited another kinase that is critically involved in this process in addition to PI3K. Indeed, Pim-1 was rapidly and strongly expressed in eosinophils after IL-5 stimulation in vitro and readily detected in eosinophils under inflammatory conditions in vivo. Moreover, by using specific protein transfer, we identified Pim-1 as a critical element in IL-5-mediated antiapoptotic signaling in eosinophils. Conclusions: Pim-1, but not PI3K, plays a major role in IL-5-mediated antiapoptotic signaling in eosinophils. (J Allergy Clin Immunol 2009;123:603-.11.)
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