Proviral integration site for Moloney murine leukemia virus 1, but not phosphatidylinositol-3 kinase, is essential in the antiapoptotic signaling cascade initiated by IL-5 in eosinophils.
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 or a 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 p110delta 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.
Andina
Nicola
N
Institute of Pharmacology, University of Bern, Bern, Switzerland.
Didichenko
Svetlana
S
Schmidt-Mende
Jan
J
Dahinden
Clemens A
CA
Simon
Hans-Uwe
HU
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004804:Eosinophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D006967:Hypersensitivity / Q000201:enzymology / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology* / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000276:immunology / Q000378:metabolism; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D020032:Tyrphostins / Q000494:pharmacology; D000077191:Wortmannin; D014966:Xanthenes / Q000494:pharmacology
D000225:Adenine; D000730:Androstadienes; D002867:Chromones; D015848:Interleukin-5; D053614:Janus Kinase 2; D009025:Morpholines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051573:Proto-Oncogene Proteins c-pim-1; D011799:Quinazolines; D020032:Tyrphostins; D000077191:Wortmannin; D014966:Xanthenes; C477872:IC 87114; C516783:SD 1029; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C507924:JAK2 protein, human; C496634:PIM1 protein, human