University of Oulu

Toll-like receptors (TLR) 4 and 2 regulate the innate immune response : study of endotoxin influence in mice

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Author: Harju, Kirsi
Organizations: University of Oulu, Faculty of Medicine, Department of Paediatrics
University of Oulu, Biocenter Oulu
Format: eBook
Online Access: PDF Full Text (PDF, 1.4 MB)
Persistent link: http://urn.fi/urn:isbn:9514273257
Language: English
Published: Oulu : University of Oulu, 2004
Publish Date: 2004-05-07
Thesis type: Doctoral Dissertation
Defence Note: Academic Dissertation to be presented with the assent of the Faculty of Medicine, University of Oulu, for public discussion in the Auditorium 12 of Oulu University Hospital, on May 7th, 2004, at 12 noon.
Reviewer: Professor Outi Vaarala
Professor Olli Vainio
Description:

Abstract

The response of the innate immune system is triggered through Toll-like transmembrane receptors (TLR) that recognize a variety of microbial products. TLR4 is the principal mediator for Gram negative bacterial endotoxin (LPS), whereas TLR2 mediates the response to Gram positive bacteria, mycobacteria, and yeast. Stimulation of TLR activates complex cascades leading first to the production of inflammatory mediators, such as proinflammatory cytokines IL-1 α/β and TNF-α.

Overproduction of inflammatory cytokines as well as failure in the activation of innate immunity are detrimental to the host. Excess inflammatory stimulation leads to a septic shock, which may cause multi-organ failure and even death. The lack of any innate response exposes the host to overwhelming bacterial infections. Appropriate regulation of the innate immune response could be a target for attempts to find therapeutics to septic shock. This experimental study focuses on functional activation of the signaling receptors TLR4 and TLR2 upon a LPS challenge.

An acute inflammation model was used for both in vivo and in vitro experiments. LPS was used to stimulate a mouse macrophage cell line. It was administred intraperitoneally or intra-amniotically to non-pregnant or time-mated mice. The basal and induced mRNA expression levels and the protein production of TLRs as well as the mRNA expression of several inflammatory mediators were studied.

The present study showed that the expression of TLR4 and TLR2 is strain and tissue-specific. At the mRNA level, the levels of TLR4 expression limited the extent of the acute cytokine response. The quality of the cytokine response was modulated by protein aggregates formed by TLR4 on the cell surface. The LPS challenge caused a marked increase in the expression of TLR2 mRNA but not the protein; the significance of this remains to be studied. The study further showed that the expression of TLRs is regulated during the perinatal period, and that the acute cytokine response to LPS in the lung develops during antenatal differentiation.

The present study provides information about how the activation of TLR regulates the acute inflammatory response and further helps to elucidate new targets for the anti-inflammatory strategies in controlling inflammatory events.


Tiivistelmä

"Toll-like"-reseptorit (TLR) ovat solukalvon proteiineja, jotka spesifisesti tunnistavat erilaisia bakteerirakenteita. Infektiossa tällainen bakteerirakenne sitoutuu reseptoriin ja seurauksena solussa käynnistyy synnynnäinen immuunivaste eli tulehdusvälittäjäaineiden tuotto. Liiallinen tulehdusvälittäjäaineiden tuotto voi johtaa septiseen shokkiin eli verenmyrkytykseen, elinvaurioihin ja jopa kuolemaan. Septisen shokin synty voisi olla estettävissä immuunivasteen voimakkuuden tarkoituksenmukaisella säätelyllä. Väitöskirjassa on tutkittu, miten TLR4 ja TLR2 aktivoituvat bakteeri-infektiossa, tarkoituksena selvittää, säätelevätkö reseptorit immuunivasteen käynnistystä ja voimakkuutta solussa.

Tutkimuksessa todettiin, että TLR4:n ja TLR2:n geenien ilmentymistä säädellään eri tavoin eri hiirikannoilla ja eri kudoksissa. TLR4-tason nousu aiheutti voimakkaamman immuunivasteen, kun taas reseptorin matala esiintymistaso laski immuunivasteen voimakkuutta. Lisäksi TLR4:aan solukalvolla sitoutuvat muut proteiinit vaikuttivat immuunivasteen laatuun. Tutkimuksessa todettiin myös, että TLR:n määrä sikiön keuhkoissa rajoittaa keuhkojen immuunivasteen kehittymistä.

Tutkimus antaa tietoa siitä, miten TL-reseptorien aktivaatio säätelee synnynnäistä immuunipuolustusta ja selventää mahdollisuutta kontrolloida immuunivasteen voimakkuutta vaikuttamalla TL-reseptoriin.


Series: Acta Universitatis Ouluensis. D, Medica
ISSN: 0355-3221
ISSN-E: 1796-2234
ISSN-L: 0355-3221
ISBN: 951-42-7325-7
ISBN Print: 951-42-7324-9
Issue: 783
Subjects:
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