Bactericidal/Permeability-Increasing Protein (BPI) and Proteinase 3: Studies at the Transcriptional Level

Sammanfattning: In myelopoiesis, neutrophils and monocytes/macrophages are formed from a common myeloid precursor cell in the bone marow. During maturation of neutrophils, cytoplasmic granules are formed in the cells and the content of these granules is critical for the function of neutrophils in the first line of defense against invading microorganisms. The Bactericidal/Permeability-Increasing protein (BPI) is stored in azurophil granules of the neutrophil and is cytotoxic against gram-negative bacteria. Absence of BPI in neutrophils of patients with Specific Granule Deficiency (SGD) and late expression of BPI at the promyelocyte stage, suggest a different regulation at the transcriptional level as compared to other azurophil granule proteins. In this thesis, we show that the transcription factors AML-1, PU.1, and Sp3 regulate the expression of human BPI in myeloid cells. We also identified a mouse ortholog to human BPI, expressed in bone marrow, testis and epididymis. However, the expression of BPI in mouse bone marrow cells is much lower than that in human bone marrow cells, indicating important differences in the transcriptional regulation. We suggest that, in contrast to human BPI, lack of C/EBP binding sites is responsible for the low expression of BPI in mouse bone marrow cells. The expression of another azurophil granule protein, human proteinase 3, is shown to be increased in myeloid cells of patients with Wegener's Granulomatosis (WG). This increased expression of proteinase 3 might be a risk factor for the development of the disease. We show that the overrepresented ?564 A/G SNP in WG patients, which introduces a new potential Sp1 transcription factor binding site, is not the reason for increased proteinase 3 expression in these patients.