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Dynamin inhibition interferes with inflammasome activation and cytokine gene expression in Streptococcus pyogenes-infected human macrophages
Natl Inst Hlth & Welf, Dept Infect Dis Surveillance & Control, Virol Unit, Helsinki, Finland.
Natl Inst Hlth & Welf, Dept Infect Dis Surveillance & Control, Virol Unit, Helsinki, Finland.
Valio Ltd R&D, Helsinki, Finland.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
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2014 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 178, no 2, 320-333 p.Article in journal (Refereed) Published
Abstract [en]

In the present study, we have analysed the ability of Streptococcus pyogenes [Group A streptococcus (GAS)] to activate the NACHT-domain-, leucinerich repeat-and PYD-containing protein 3 (NALP3) inflammasome complex in human monocyte-derived macrophages and the molecules and signalling pathways involved in GAS-induced inflammatory responses. We focused upon analysing the impact of dynamin-dependent endocytosis and the role of major streptococcal virulence factors streptolysin O (SLO) and streptolysin S (SLS) in the immune responses induced by GAS. These virulence factors are involved in immune evasion by forming pores in host cell membranes, and aid the bacteria to escape from the endosome-lysosome pathway. We analysed cytokine gene expression in human primary macrophages after stimulation with live or inactivated wild-type GAS as well as with live SLO and SLS defective bacteria. Interleukin (IL)-1 beta, IL-10, tumour necrosis factor (TNF)-alpha and chemokine (C-X-C motif) ligand (CXCL)-10 cytokines were produced after bacterial stimulation in a dose-dependent manner and no differences in cytokine levels were seen between live, inactivated or mutant bacteria. These data suggest that streptolysins or other secreted bacterial products are not required for the inflammatory responses induced by GAS. Our data indicate that inhibition of dynamin-dependent endocytosis in macrophages attenuates the induction of IL-1 beta, TNF-alpha, interferon (IFN)-beta and CXCL-10 mRNAs. We also observed that pro-IL-1 beta protein was expressed and efficiently cleaved into mature-IL-1 beta via inflammasome activation after bacterial stimulation. Furthermore, we demonstrate that multiple signalling pathways are involved in GAS-stimulated inflammatory responses in human macrophages.

Place, publisher, year, edition, pages
2014. Vol. 178, no 2, 320-333 p.
Keyword [en]
cytokine, gene regulation, inflammasome, innate immunity, signal transduction
National Category
Immunology in the medical area
URN: urn:nbn:se:umu:diva-95858DOI: 10.1111/cei.12425ISI: 000342915800013OAI: diva2:768382
Available from: 2014-12-03 Created: 2014-11-06 Last updated: 2014-12-03Bibliographically approved

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Charpentier, Emmanuelle
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