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Signalling and trafficking of the cysteinyl leukotriene receptors in intestinal epithelial cells

Parhamifar, Ladan LU (2009) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2009:8.
Abstract
Inflammation is a response to injury or pathogen invasion. A large proportion of the bodie's immune system is centred in the gastrointestinal tract (GI). Prolonged inflammatory conditions of the GI have been suggested to increase the risk for developing colon cancer. The cysteinyl leukotrienes (CysLTs), LTC4, LTD4 and LTE4 are inflammatory mediators that can bind to four known receptors, two of which are the CysLT1R and CysLT2R. Inhibitors of the CysLT1R are currently used in the clinic as asthma medication. LTD4 has been shown to induce cell proliferation, survival and migration in intestinal epithelial cells (Int407) via the CysLT1R. These mechanisms are often used by cancer cells to surive and spread. Furthermore, increased expression... (More)
Inflammation is a response to injury or pathogen invasion. A large proportion of the bodie's immune system is centred in the gastrointestinal tract (GI). Prolonged inflammatory conditions of the GI have been suggested to increase the risk for developing colon cancer. The cysteinyl leukotrienes (CysLTs), LTC4, LTD4 and LTE4 are inflammatory mediators that can bind to four known receptors, two of which are the CysLT1R and CysLT2R. Inhibitors of the CysLT1R are currently used in the clinic as asthma medication. LTD4 has been shown to induce cell proliferation, survival and migration in intestinal epithelial cells (Int407) via the CysLT1R. These mechanisms are often used by cancer cells to surive and spread. Furthermore, increased expression of the CysLT1R in colon cancer patient material is correlated with a poorer survival prognosis. Conversley, increased expression of the CysLT2R is correlated with a better survival prognosis. The aim of this thesis was therefore to explore the signalling and trafficking of the cysLT1R and CysLT2R. Our results demonstrate that LTD4 via the CysLT1R can activate the enzyme cPLA2-alpha. This enzyme releases arachidonic acid, the precursor of CysLTs, from the cell membranes, upon activation. One major regulatory mechanism of GPCRs is the internalization from cell membrane upon activation. We demonstrate how LTD4 mainly internalizes CysLT1R and accumulates this receptor at the nuclear membrane and that LTC4 internalizes both the CysLT1R and CysLT2R. This information is valuable in developing potential drugtargets aqainst CysLT1 and CysLT2 in cancer and inflammation. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Godson, Catherine, College of life sciences, Conway Institute
organization
publishing date
type
Thesis
publication status
published
subject
keywords
trafficking, Cysteinyl leukotriene receptors, inflammation, cytosolic phospholipase A2, colon cancer
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2009:8
pages
139 pages
publisher
Department of Laboratory Medicine, Lund University
defense location
Main lecture hall, pathology building, ent 78 UMAS, Malmö
defense date
2009-01-23 09:15
ISSN
1652-8220
ISBN
978-91-86059-95-8
language
English
LU publication?
yes
id
6b9b0641-bb61-4659-a399-f7e79a96bd44 (old id 1275267)
date added to LUP
2009-01-08 13:42:45
date last changed
2016-09-19 08:44:47
@phdthesis{6b9b0641-bb61-4659-a399-f7e79a96bd44,
  abstract     = {Inflammation is a response to injury or pathogen invasion. A large proportion of the bodie's immune system is centred in the gastrointestinal tract (GI). Prolonged inflammatory conditions of the GI have been suggested to increase the risk for developing colon cancer. The cysteinyl leukotrienes (CysLTs), LTC4, LTD4 and LTE4 are inflammatory mediators that can bind to four known receptors, two of which are the CysLT1R and CysLT2R. Inhibitors of the CysLT1R are currently used in the clinic as asthma medication. LTD4 has been shown to induce cell proliferation, survival and migration in intestinal epithelial cells (Int407) via the CysLT1R. These mechanisms are often used by cancer cells to surive and spread. Furthermore, increased expression of the CysLT1R in colon cancer patient material is correlated with a poorer survival prognosis. Conversley, increased expression of the CysLT2R is correlated with a better survival prognosis. The aim of this thesis was therefore to explore the signalling and trafficking of the cysLT1R and CysLT2R. Our results demonstrate that LTD4 via the CysLT1R can activate the enzyme cPLA2-alpha. This enzyme releases arachidonic acid, the precursor of CysLTs, from the cell membranes, upon activation. One major regulatory mechanism of GPCRs is the internalization from cell membrane upon activation. We demonstrate how LTD4 mainly internalizes CysLT1R and accumulates this receptor at the nuclear membrane and that LTC4 internalizes both the CysLT1R and CysLT2R. This information is valuable in developing potential drugtargets aqainst CysLT1 and CysLT2 in cancer and inflammation.},
  author       = {Parhamifar, Ladan},
  isbn         = {978-91-86059-95-8},
  issn         = {1652-8220},
  keyword      = {trafficking,Cysteinyl leukotriene receptors,inflammation,cytosolic phospholipase A2,colon cancer},
  language     = {eng},
  pages        = {139},
  publisher    = {Department of Laboratory Medicine, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Signalling and trafficking of the cysteinyl leukotriene receptors in intestinal epithelial cells},
  volume       = {2009:8},
  year         = {2009},
}