TNFalpha expression in monocytes/macrophages

Karolina Andersson

Research output: ThesisDoctoral Thesis (compilation)

63 Downloads (Pure)

Abstract

The recognition of microbes or microbial products by leukocytes is a key event in innate immunity. Binding of microbial products to cell surface receptors on phagocytes induce a response that includes the production of inflammatory mediators. One such mediator is the cytokine tumour necrosis factor alpha (TNF). TNF is a pleotropic cytokine with actions ranging from tissue injury to septic chock. This thesis is based on studies performed with the use of different stimuli (either bacteria, the bacterial product LPS or direct activators of protein kinases) which induce TNF production in cells of the monocytic lineage. The main focus has been to study the signal transduction pathway regulating TNF expression.

Dexamethasone, a synthetic glucocorticoid, inhibits bacteria-induced TNF production in mouse macrophages. Effects on TNF expression when cells are pretreated with dexamethasone are a decrease in gene transcription as well as posttranscriptional inhibition. Okadaic acid, a protein phosphatase inhibitor, seems to overcome the posttranscriptional inhibition exerted by dexamethasone when TNF expression is induced.

The posttranscriptional regulation of TNF was further studied in human monocytic THP-1 cells. THP-1 cells express TNF mRNA when unstimulated, but produce no TNF protein. Induction of TNF production can be achieved by activation of the classical MAP kinase or p38 MAP kinase pathways without any significant change in gene transcription.

TNF mRNA expression is not detectable in primary mouse macrophages but when challenged with LPS, TNF mRNA and subsequent protein production increases. TNF production is regulated both at the level of gene transcription and translation of the transcripts. The kinase Mnk1, activated by ERK and/or p38, phosphorylates the translation initiation factor eIF4E and this correlates with TNF production. A proposed signalling pathway to translational regulation of TNF in mouse macrophages is presented.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Experimental Medical Science
Supervisors/Advisors
  • Sundler, Roger, Supervisor
Award date2005 May 19
Publisher
Print ISBNs91-628-6507-2
Publication statusPublished - 2005

Bibliographical note

Defence details

Date: 2005-05-19
Time: 09:15
Place: Grubb-salen, BMC, Sölvegatan 19, Lund

External reviewer(s)

Name: Rasmusson, Birgitta
Title: Associate Professor
Affiliation: Department of Molecular and Clinical Medicine,University Hospital of Linköping

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<div class="article_info">K Gewert, U Svensson, K Andersson, E Holst and R Sundler. <span class="article_issue_date">1999</span>. <span class="article_title">Dexamethasone differentially regulates cytokine transcription and translation in macrophages responding to bacteria or okadaic acid</span> <span class="journal_series_title">Cell signal</span>, <span class="journal_volume">vol 11</span> <span class="journal_pages">pp 665-70</span>.</div>
<div class="article_info">K Andersson and R Sundler. <span class="article_issue_date">2000</span>. <span class="article_title">Signalling to translational activation of tumour necrosis factor-alpha expression in human THP-1 cells</span> <span class="journal_series_title">Cytokine</span>, <span class="journal_volume">vol 12</span> <span class="journal_pages">pp 1784-87</span>.</div>
<div class="article_info">K Andersson and R Sundler. <span class="article_issue_date"></span>. <span class="article_title">Posttranscriptional regulation of TNFalpha expression via eukaryotic initiation factor 4E (eIF4E)phosphorylation in mouse macrophages</span> (submitted)</div>

Subject classification (UKÄ)

  • Basic Medicine

Keywords

  • Biomedicinska vetenskaper (allmänt)
  • General biomedical sciences
  • Protein kinase
  • Macrophage
  • TNF

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