Analysis of the impact of Bruton tyrosine kinase on myeloid cell development and function
Auch gedruckt in der BibliothekZ: J-H 14.280; W: W-H 12.732
FakultätFakultät für Naturwissenschaften
Ressourcen- / MedientypDissertation, Text
Datum der Freischaltung2011-12-08
In the present study, it could be demonstrated that Bruton tyrosine kinase is not only necessary for the proper hematopoietic differentiation of B cells, but also of granulocytes and monocytes downstream of the granulocyte-macrophage progenitor (GMP) in the bone marrow. We could show that GMP isolated from the bone marrow of Btk-deficient mice preferentially developed into granulocytes at the expense of monocytes or undifferentiated cells when cultivated in the presence of granulocyte-monocyte-colony stimulating factor (GM-CSF) or TLR-ligands as differentiation cues. In addition, the enhanced granulopoiesis could be confirmed by the evaluation of the bone marrow compartment of Btk-mutant mice. With respect to the terminal differentiation of granulocytes in the bone marrow we also found a substantial maturation defect in granulocytes obtained from Btk-deficient mice, although the granulopoiesis was enhanced in these mice. This immature phenotype of granulocytes was associated with an inefficient development of granules as well as a reduced expression of granule proteins, like myeloperoxidase, neutrophil elastase, lactoferrin or gelatinase. Moreover, analyzes of neutrophil function in the reverse passive Arthus reaction demonstrated a significant impairment of Btk-deficient neutrophils in tissue migration at the site of immune complex deposition. The examination of the molecular mechanism revealed a decreased phosphorylation of the regulatory subunit p85 of the phosphatidylinositol-3-kinase, Akt and glycogen synthase kinase-3ß in Btk-deficient myeloid cells after GM-CSF engagement, where Btk is activated in wild type cells. In addition, we could show that the expression of the lineage-determining transcription factors CAAT-enhancer binding protein alpha (C/EBPalpha) and PU.1 is diminished in Btk-deficient bone marrow cells.
LizenzStandard (Fassung vom 01.10.2008)
MeSHBruton's tyrosine kinase