Signal transducer and activator of transcription 5a (STAT5a) is required for eosinophil differentiation of human cord blood–derived CD34+ cells

Abstract

IntroductionEosinophils play an important role in immunity against helminth infection. Parasite infection results in enhanced eosinophil numbers and in migration toward and degranulation at the site of parasite invasion. In vitro studies demonstrated that eosinophils are capable of adhering to parasites in the presence of different antibody isotypes (immunoglobulin E [IgE], IgG, IgA) 1,2 and complement components (C3b). 3 At the site of contact, eosinophils degranulate, resulting in damage to the tegumental membranes and eventually in the death of parasites. 4 The toxic effect of eosinophilic granule proteins, such as eosinophilic cationic protein (ECP), is complemented by the generation of toxic oxygen metabolites. 5 Besides their role in immunity against parasitic infection, eosinophils are thought to play an important role in the pathogenesis of allergic diseases, among them asthma and dermatitis. Eosinophils are recruited to the site of allergic inflammation by chemoattractants, such as C5a and platelet activating factor (PAF). 6,7 Release of granular contents at the inflammatory locus can result in long-term tissue damage. For example, airway epithelium can be damaged during airway inflammation. 8,9 Eosinophils are derived from pluripotent hematopoietic stem cells (HSCs) in the bone marrow. These progenitors are defined as precursors for all lineages of mature blood cells, and they are capable of self-renewal. Such cells can be divided into long-term repopulating hematopoietic stem cells (LT-HSCs) and short-term repopulating hematopoietic stem cells (ST-HSCs). ST-HSCs can differentiate to multipotent progenitor cells, which are capable of differentiation toward a subset of the hematopoietic lineage. These multipotent stem cells include the common lymphoid precursor 10 and the common myeloid precursor. 11 Common myeloid progenitor cells, known as the granulocyte/erythrocyte/macrophage/ megakaryocyte colony-forming unit (CFU-GEMM), can differentiate toward the erythroid, megakaryocytic, and myelomonocytic lineage. It has been demonstrated that genes specific for erythroid, myeloid, or megakaryocytic lineages are transcribed in the common myeloid progenitors before commitment to a single lineage. Genes specific for differentiation toward other lineages are downregulated on commitment to a single lineage. 12 Myeloid differentiation is regulated by a variety of cytokines, including erythropoietin (EPO), granulocyte-colony-stimulating factor (G-CSF), thrombopoietin (TPO), interleukin-3 (IL-3), granulocyte macrophagecolony-stimulating factor (GM-CSF), macrophage-colony-stimulating factor (M-CSF), and IL-5. IL-3 and GM-CSF are cytokines that regulate proliferation and survival during myeloid differentiation of various lineages, whereas EPO, TPO, G-CSF, M-CSF, and IL-5 are required for the final maturation of erythrocytes, 13 megakaryocytes, platelets, 14,15 neutrophils, monocytes, 16 and eosinophils, 17,18 respectively.Hematopoietic cytokines can activate several signal transduction pathways, including the Ras/Raf/...

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

“…STAT5 has been shown to promote both survival and differentiation in a number of cells, including hematopoietic and mammary cells (Nosaka et al, 1999;Buitenhuis et al, 2003;Cui et al, 2004). Recently, the critical role of STAT5a in promoting survival and differentiation of hematopoietic stem cells has been demonstrated (Schuringa et al, 2004).…”

Tight Control of STAT5 Activity Determines Human CD34-Derived Interstitial Dendritic Cell and Langerhans Cell Development

“…The used vectors contained wildtype STAT5a (STAT5a-wt) (17); STAT5a1*6, a constitutively active STAT5a mutant that harbors two point mutations, one in the transactivation domain (S710F) and the other in the DNA-binding domain (H298R) (16); or STAT5aD750, a dominant-negative STAT5a mutant that can bind to DNA but is unable to activate transcription (17,25). A vector expressing only IRES followed by eGFP was used as negative control.…”

“…Most myeloid cells express cytokine receptors that are able to induce STAT5 activation, and STAT5 has been shown to regulate the development of various myeloid lineages (13,17). GM-CSF is one of the cytokines triggering STAT5 phosphorylation via activation of JAK2 (18).…”

Homeostatic Intracellular-Free Ca2+ Is Permissive for Rap1-Mediated Constitutive Activation of α4 Integrins on Eosinophils

“…ϩ cells CD34 ϩ cells were isolated as previously described (24). Mononuclear cells were isolated from umbilical cord blood by density centrifugation over isotonic Ficoll solution (Pharmacia).…”