Regulation of neutrophil apoptosis

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The human neutrophil is the most abundant granulocyte and the major type of cell involved in an acute inflammatory response. Neutrophils are armed with various systems of enzymes, that can find and kill pathogens, but unfortunately, these "weapons" cannot distinguish between the host tissues and the "invaders." Therefore, an extensive neutrophil reaction leads to continuous release of toxic metabolites, which causes successive self-destruction of host tissues and possibly also organ failure. Such a series of destructive events has been implicated in diseases such as rheumatoid arthritis, myocardial infarction/reperfusion injury, atherogenesis, asthma, cystic fibrosis, emphysema, and vasculitis. Resolution of an acute inflammatory process depends on termination of neutrophil emigration from blood vessels and clearance of extravasated neutrophils and their metabolic products. Outside the blood vessels, neutrophils spontaneously undergo apoptosis, and are therefore removed by phagocytic cells at the site of inflammation. Neutrophil apoptosis can be modulated by several factors in the local environment, such as the Fas ligand (FasL), but the molecular mechanisms involved are poorly understood.

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.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Pathology, Malmö
Supervisors/Advisors
  • [unknown], [unknown], Supervisor, External person
Award date2004 Apr 23
Publisher
ISBN (Print)91-89625-31-5
Publication statusPublished - 2004

Bibliographical note

Defence details

Date: 2004-04-23
Time: 10:15
Place: main lecture hall, Pathology building, Malmö university hospital

External reviewer(s)

Name: Coffer, Paul
Title: [unknown]
Affiliation: [unknown]

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Article: I. Maria Alvarado Kristensson, M. Isabella Pörn-Ares, Simone Grethe, David Smith, Limin Zheng and Tommy Andersson.“p38 Mitogen-activated protein kinase and phosphatidylinositol 3-kinase activities have opposite effects on human neutrophil apoptosis”,FASEB J. (November 29, 2001) 10.1096/fj.01-0817fje.

Article: II. Maria Alvarado Kristensson, Fredrik Melander, Karin Leandersson, Lars Rönnstrand, Christer Wernstedt and Tommy Andersson.“p38-MAPK signals survival by phosphorylation of caspase-8 and caspase-3 in human neutrophils”,J. Exp. Med. 199 (2004), 449-458.

Article: III. Maria Alvarado Kristensson and Tommy Andersson. “Protein Phosphatase 2A regulates neutrophils apoptosis by dephosphorylation and deactivation of p38 MAPK”, manuscript.

Subject classification (UKÄ)

  • 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

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