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Published online before print October 26, 2007

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(Journal of Leukocyte Biology. 2008;83:393-400.)
© 2008 by Society for Leukocyte Biology

Terminally differentiated neutrophils predominantly express Survivin-2, a dominant-negative isoform of Survivin

Huiyuan Hu^*,, Yayoi Shikama^*,1, Isao Matsuoka^*, and Junko Kimura^*

^* Department of Pharmacology, Fukushima Medical University School of Medicine, Fukushima, Japan;
Department of Pharmacology, China Medical University, Shenyang, China; and
Laboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan

¹ Correspondence: Department of Pharmacology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, 960-1295, Japan. E-mail: yayois{at}fmu.ac.jp

Survivin, which is a member of the inhibitor of apoptosis protein family, was found originally in immature cells and cancer cells but not in non-neoplastic adult tissues. The subsequent identification of four other alternative splice variants that possess distinct functions and localizations suggested the diverse roles of survivin isoforms. An unspecified isoform of survivin was found recently to be induced in terminally differentiated neutrophils by cytokines that prolong the neutrophil lifespan, such as GM-CSF and G-CSF, suggesting the importance of survivin in blocking apoptosis in neutrophils. To examine the mechanism by which survivin inhibits neutrophil apoptosis, we attempted to induce survivin by GM-CSF/G-CSF in an HL60 cell line that was differentiated into neutrophils by all-trans retinoic acid and DMSO and freshly isolated human neutrophils. The antiapoptotic isoform "Survivin," which was decreased during differentiation, was re-induced by GM-CSF in neutrophil-like, differentiated HL60. In contrast, in normal neutrophils, survivin mRNA was observed to increase spontaneously after 24 h incubation, and no additional elevation was induced by GM-CSF/G-CSF, which exerted their antiapoptotic effects on the neutrophils in 6 h, despite the lack of survivin induction. PCR and Western blotting detected Survivin-2, a dominant-negative of antiapoptotic Survivin, with no other isoforms in the freshly isolated or incubated neutrophils. Our study revealed that the expressed isoforms and the response to GM-CSF were different between the HL60-derived and normal neutrophils, which predominantly expressed Survivin-2, not likely involved in apoptosis inhibition by GM-CSF/G-CSF.

Key Words: splice variant • apoptosis inhibition • neutrophilic granulocytes • cytokines