Regulation of neutrophil apoptosis
Author
Summary, in English
In this dissertation thesis, I describe and elucidate intracellular signalling mechanisms that are involved in regulation of spontaneous and Fas-induced apoptosis in human neutrophils. Using two different methods it was possible to detect constitutive activity of p38 mitogen-activated protein kinase (p38) in newly isolated neutrophils. The p38 survival signal was transiently lost during both spontaneous and Fas-induced apoptosis, favoured induction of the apoptotic process. During the transient loss of p38 activity there was a temporary Fas-induced increase in phosphatidylinositol 3-kinase (PI3K) activity, which also had a pro-apoptotic impact on the neutrophils. In addition, my experiments showed that the active form of p38 associates with caspase 8 and caspase 3, which is necessary for p38-induced phosphorylation of serine-362 and serine-150 on these caspases. These biochemical modifications impair the activities, and possibly also the stability, of caspase 8 and 3 and thereby weaken the capacity of these enzymes to induce apoptosis. The results in this dissertation also demonstrate that the protein phosphatase type 2A (PP2A) can directly and independently decrease the phosphorylation levels of both p38 and caspase 3. Consequently, PP2A can increase the activity of caspase 3 by dual mechanisms and thereby promote the apoptotic response in human neutrophils.
Department/s
Publishing year
2004
Language
English
Document type
Dissertation
Publisher
Maria Alvarado-Kristensson, experimentall pathology, Lund University, U-MAS, entrance 78, 205 02 Malmö,
Topic
- Cancer and Oncology
- Cell and Molecular Biology
Keywords
- General pathology
- pathological anatomy
- Patologi (allmän)
- patologisk anatomi
- PP2A
- p38 MAPK
- caspases
- signal transduction
- inflammation
- Apoptosis
- human neutrophils
Status
Published
Research group
- Molecular Pathology, Malmö
- Pathology, Malmö
Supervisor
- [unknown] [unknown]
ISBN/ISSN/Other
- ISBN: 91-89625-31-5
Defence date
23 April 2004
Defence time
10:15
Defence place
main lecture hall, Pathology building, Malmö university hospital
Opponent
- Paul Coffer