IL-3 induces a Pim1-dependent antiapoptotic pathway in primary human basophils

Abstract

IntroductionApoptosis of granulocytes and subsequent clearance of apoptotic cells are important processes for the successful resolution of acute and chronic inflammation. Basophils represent the least abundant granulocyte population and are considered as key effector cells in Th2-type, IgE-associated allergic disorders as well as in protective immune responses to helmints. Pro-inflammatory and immunomodulatory activities of basophils include secretion of histamine and the lipid mediator leukotriene C 4 as well as rapid production of interleukin-4 (IL-4) and IL-13, Th2-type cytokines crucial for the development of allergy and asthma. Positive regulators of basophil mediator release and cytokine production have been described, whereas attempts to find negative regulators of basophil cellular functions have been unsuccessful. Therefore, the modulation of basophil apoptosis probably has a particularly high impact on the outcome of allergic inflammation.Cytokines of granulocyte-macrophage colony-stimulating factor (GM-CSF) subfamily (GM-CSF, IL-5, and IL-3) support granulocyte survival in a granulocyte-type-restricted manner. [1][2][3][4][5][6] Modulation of neutrophil and eosinophil apoptosis mediated by these cytokines has been suggested to rely on the up-regulation of antiapoptotic proteins of the Bcl-2 family, such as Bcl-2, Bcl-X L , Mcl-1 and A1, 7-9 as well as IAP family proteins. [10][11][12] With regards to signaling pathways, Janus kinase (JAK)/signal transducer and activator of transcription 3 and 5 (Stat3/Stat5), phosphatidylinositol 3-kinase (PI3-kinase), as well as p38-mitogen-activated protein kinase (MAPK) have been implicated in the regulation of neutrophil and eosinophil apoptosis by GM-CSF, IL-5, and IL-3. [13][14][15][16][17][18][19] Although previous studies showed that IL-3 prolongs the life span of basophils, 5,6 there is a complete lack of knowledge about the proteins and the mechanisms that regulate spontaneous and cytokineenhanced survival of basophils. A single report suggested a requirement of PI3-kinase signaling for IL-3-mediated basophil survival. 6 The mechanisms of IL-3 signaling and the involvement of downstream targets regulating cell proliferation and survival have been most thoroughly studied in leukemic human cell lines and IL-3-dependent cell lines from genetically manipulated mice. Most papers highlight the requirement of the PI3-kinase/Akt (PKB) signaling pathway and mainly differ in their interpretations about the relative importance of downstream targets, such as Bad, FOXO3, and NF-B. 20-24 These findings cannot always be transferred to human basophils or other nondividing leukocytes because the regulation of survival strongly depends on the cellular background. Furthermore, the mechanisms regulating proliferation or apoptosis are difficult to distinguish in proliferating cells, and transformed cell lines may display disturbed signaling pathways. It is thus necessary to study primary blood basophils ex vivo to understand the mechanisms regulating their survival, despite inhe...

Signaling pathways activated by a protease allergen in basophils

“…IL-3 has been shown to play many roles in basophil functioning, because it can lead to direct basophil cytokine production (24), play a key role in basophil expansion and survival (28,29), and also can enhance the stimulatory activity of many basophil activators in vitro (30,31). Because IL-3 is used as a growth factor in our in vitro basophil cultures and because of its published role in signaling through the FcRγ-chain (24), we wanted to determine if IL-3 is required for responsiveness to papain.…”

A progenitor cell origin of myeloid malignancies

“…The spontaneous mutation rate per gene per cell division is approximately given by 0.5 to 2.0 ϫ10 Ϫ7 (40,41). Time in our model is measured in days because each time step in the model is equivalent to the turnover time of the most differentiated cell level, which is approximately a day (42). We set 60 years (t Ϸ 20,000 days) as the upper bound for our consideration because the median age of diagnosis of Polycythemia Vera is 60 years (43) and the MPN-initiating cell must have emerged before diagnosis.…”

Critical Evaluation of Antiepileptic Drugs in Epileptic Pregnant Women - Hungarian Experiences

“…Much like AKT, enforced expression of Pim-2 results in prolonged survival of at least some cells after IL-3 deprivation [43]. The related kinase Pim-1 may also transduce survival signal in basophils that permits survival in the absence of IL-3 [44]. Over-expression of an activated form of Ras blocked IL-3 withdrawal induced apoptosis without inducing significant IL-3 independent proliferation in an IL-3 dependent cells line [45].…”