Streptococcus pneumoniae stabilizes tumor necrosis factor α mRNA through a pathway dependent on p38 MAPK but independent of Toll-like receptors

Trine H Mogensen,Søren R Paludan,Lars Østergaard,Randi S Berg

doi:10.1186/1471-2172-9-52

Trine H Mogensen, Søren R Paludan + Show 2 more

Open Access

https://doi.org/10.1186/1471-2172-9-52

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Journal: BMC immunology	Publication Date: Jan 1, 2008
Citations: 40	License type: cc-by

Affiliation: Aarhus University Hospital, Aarhus University

Abstract

BackgroundStreptococcus pneumoniae is a human pathogenic bacteria and a major cause of severe invasive diseases, including pneumonia, bacteremia, and meningitis. Infections with S. pneumoniae evoke a strong inflammatory response, which plays a major role in the pathogenesis of pneumococcal disease.ResultsIn this study, we have examined how S. pneumoniae affects expression of the inflammatory cytokine tumor necrosis factor (TNF) α, and the molecular mechanisms involved. Secretion of TNF-α was strongly induced by S. pneumoniae, which was able to stabilize TNF-α mRNA through a mechanism dependent on the viability of the bacteria as well as the adenylate uridylate-rich elements in the 3'untranslated region of TNF-α mRNA. The ability of S. pneumoniae to stabilize TNF-α mRNA was dependent on the mitogen-activated protein kinase (MAPK) p38 whereas inhibition of Toll-like receptor signaling via MyD88 did not affect S. pneumoniae-induced mRNA stabilization. P38 was activated through a pathway involving the upstream kinase transforming growth factor-activated kinase 1 and MAPK kinase 3.ConclusionThus, S. pneumoniae stabilizes TNF-α mRNA through a pathway dependent on p38 but independent of Toll-like receptors. Production of TNF-α may contribute significantly to the inflammatory response raised during pneumococcal infection.

Highlights

Streptococcus pneumoniae is a human pathogenic bacteria and a major cause of severe invasive diseases, including pneumonia, bacteremia, and meningitis
To examine whether the adenylate uridylate rich elements (ARE) of the tumor necrosis factor (TNF)-α mRNA were required for the observed effect, we turned to a cell system derived from RAW264.7 cells, consisting of two cell lines stably expressing a reporter gene, transcribed from a constitutive promoter
When the RAW TNF-α 3'-untranslated region (UTR) adenylate uridylate (AU)+ cell line was incubated in the presence of S. pneumoniae, a very strong increase in chloramphenicol acetyl transferase (CAT) levels was observed (Fig. 1C), whereas LPS and N. meningitidis affected accumulation of CAT protein only to a more modest extent

Summary

Introduction

Streptococcus pneumoniae is a human pathogenic bacteria and a major cause of severe invasive diseases, including pneumonia, bacteremia, and meningitis. Infections with S. pneumoniae evoke a strong inflammatory response, which plays a major role in the pathogenesis of pneumococcal disease. Streptococcus pneumoniae is an important cause of severe invasive infections, including pneumonia, bacteremia, and meningitis [1,2]. TNF-α plays an important role in activation and recruitment of leukocytes to inflamed tissue [6], and has been demonstrated to be involved in the host-defense against a number of important human pathogens, including S. pneumoniae [7,8,9]. TNF-α is associated with excessive inflammation and immunopathology in infections and autoimmune diseases, and TNF-a has been suggested to be involved in breakage of the blood-brain barrier during development of hematogenous pneumococcal meningitis [10]

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