Regulation of the cytoskeleton and the adhesiveness of intestinal epithelial cells by leukotriene D4

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Leukotrienes belong to a family of biologically active conjugated trienes that are formed from arachidonic acid via the 5-lipoxygenase pathway and are important mediators of inflammatory reactions. The CysLT1 receptor that specifically serves as receptor for leukotriene D4 (LTD4) has been identified as a G-protein coupled receptor.

Cell-cell and cell-matrix complexes of epithelial cells are interconnected through cytoskeletal filaments and proteins, and they influence the activities and outcome of various cellular processes. This thesis is focused primarily on the effect that LTD4 has on reorganisation of the actin cytoskeleton and on cell-cell and cell-matrix adhesion properties. We found that LTD4 caused dramatic changes in the actin cytoskeleton in intestinal epithelial cells, and an important factor in this context was the impact of this leukotriene on the actin-binding protein vinculin, which included inducing translocation of vinculin from a cell-cell to a cell-matrix complex.

In general, cell adhesion favours cell survival signalling, and integrins are the main receptors responsible for mediating the attachment of different types of cells to matrix proteins. We have unequivocally established that direct signalling occurs between the LTD4 receptor and the collagen integrins in two different cell lines respectively derived from human colon carcinoma and intestinal epithelial cells. Increased adhesion of the cancer cells depended on activation of cyclooxygenase-2, an enzyme that is involved in progression of colon cancers, whereas adhesion of the intestinal epithelial cells was augmented by LTD4-induced translocation of protein kinase C to areas where integrins bind to matrix proteins (focal adhesions). In conclusion, inflammatory mediators such as LTD4 can affect cell survival through their impact on specific integrins.

Details

Authors
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • oncology, Cytology, patologisk anatomi, Patologi (allmän), pathological anatomy, General pathology, PKC, vinculin, actin filament, focal adhesion, LTD4, integrin, cancerology, Cytologi, onkologi, cancer, Biochemistry, Metabolism, Biokemi, metabolism
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date2002 May 24
Publisher
  • Anita Sjölander, Depatment of Laboratory Medicine, Division of Experimental Pathology, Malmö University Hospital, Malmö, Sweden,
Print ISBNs91-628-5242-6
Publication statusPublished - 2002
Publication categoryResearch

Bibliographic note

Defence details Date: 2002-05-24 Time: 10:15 Place: "Lilla Aulan", Medicinsk Forskningscentrum, Malmö University Hospital External reviewer(s) Name: Johansson, Staffan Title: Prof Affiliation: Uppsala --- Article: 1. Ramin Massoumi and Anita Sjölander., The inflammatory mediator leukotriene D4 triggers a rapid reorganisation of the actin cytoskeleton in human intestinal epithelial cells. European Journal of Cell Biology 75:185-191 (1998). Article: 2. Ramin Massoumi and Anita Sjölander., Leukotriene D4 affects localisation of vinculin in intestinal epithelial cells via distinct tyrosine kinase and protein kinase C controlled events. Journal of Cell Science 114:1925-1934 (2001). Article: 3. Charles Kumar Thodetti, Ramin Massoumi, Lene Bindslev, and Anita Sjölander., LTD4 induces activation and association of RhoA with a Gbg-PLCg1 complex in intestinal epithelial cells. Biochemical Journal. In press (2002). Article: 4. Ramin Massoumi, Christer Larsson, and Anita Sjölander., LTD4 induces stress fibre formation via activation of RhoA and PKC-delta in intestinal epithelial cells. Manuscript. Article: 5. Ramin Massoumi, Christian Kamp Nilsson, Denijal Azemovic, and Anita Sjölander., Leukotriene D4-induced cell adhesion is mediated through Prostaglandin E2 production and upregulation of alpha2 beta1 integrin in Caco-2 cells. Manuscript.