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Blood, 15 November 2008, Vol. 112, No. 10, pp. 3949-3958.
Prepublished online as a Blood First Edition Paper on September 2, 2008; DOI 10.1182/blood-2008-04-149419.
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Submitted April 4, 2008
Accepted August 5, 2008
IL-3 induces a Pim1-dependent anti-apoptotic pathway in primary human basophils
Svetlana A Didichenko, Nicole Spiegl, Thomas Brunner, and Clemens A Dahinden*
Insitute of Immunology, University of Bern, Inselspital, Bern, Switzerland
Institute of Pathology, Univeristy of Bern, Bern, Switzerland
* Corresponding author; email: clemens.dahinden{at}iib.unibe.ch.
The contribution of basophils in allergic disease and other Th2-type immune responses depends on their persistence at sites of inflammation, but the ligands and molecular pathways supporting basophil survival are largely unknown. The comparison of rates of apoptosis and of the expression of anti-apoptotic proteins in different human granulocyte types revealed that basophils have a considerably longer spontaneous live span than neutrophils and eosinophils consistent with high levels of constitutive Bcl-2 expression. IL-3 is the only ligand that efficiently protects basophils from apoptosis as evidenced by screening a large number of stimuli. IL-3 up-regulates the expression of the anti-apoptotic proteins cIAP2, Mcl-1 and Bcl-XL, and induces a rapid and sustained de novo expression of the serine/threonine kinase Pim1 that closely correlates with cytokine-enhanced survival. Inhibitor studies and protein transduction of primary basophils using wild-type and kinase-dead Pim1-Tat fusion-proteins demonstrate the functional importance of Pim1 induction in the IL-3-enhanced survival. Our data further indicate that the anti-apoptotic Pim1-mediated pathway operates independently of PI3-kinase but involves the activation of p38 MAPK. The induction of Pim1 leading to PI3-kinase-independent survival as described here for basophils may also be a relevant anti-apoptotic mechanism in other terminally differentiated leukocyte types.
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