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Schistosome larvae stimulate macrophage cytokine production through TLR4-dependent and -independent pathways.

ABSTRACT: Exposure of the mammalian host to infective larvae of Schistosoma mansoni causes an acute inflammatory response in the skin and the activation of several cell types of the innate immune response including macrophages. Using an in vitro model of macrophage activation, we show that schistosome larvae possess molecules that directly stimulate both thioglycollate-elicited macrophages (tM) and IFNgamma-activated tM in vitro to produce several cytokines including IL-6, IL-12p40 and IL-10. The parasite-derived molecules are enriched within the material released by the parasite following transformation [0- to 3-h released larval preparation (0-3hRP)] but not within soluble preparations of whole larvae. Cytokine production was maintained in the presence of polymyxin B, confirming that contaminating endotoxin was not responsible. IL-12p40 and IL-10 production was much lower by cells from C3H/HeJ mice, which have defective Toll-like receptor 4 (TLR4), but IL-6 production was unaffected. Experiments using TLR4-/- mice confirmed that IL-12p40 production by tM in response to 0-3hRP was partly dependent upon functional TLR4, whereas IL-6 production was entirely independent. In contrast, tM from MyD88-/- mice failed to secrete either IL-12p40 or IL-6, underlining a pivotal role of TLR signalling in cytokine production by macrophages in response to stimulation with 0-3hRP. Finally, we show that glycan components of 0-3hRP are required for optimal cytokine production since protease treatment of 0-3hRP had no effect on IL-12p40 production and only a slight effect on IL-6, while sodium meta-periodate treatment almost completely abolished production of both cytokines.

SUBMITTER: Jenkins SJ

PROVIDER: S-EPMC1950773 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Schistosome larvae stimulate macrophage cytokine production through TLR4-dependent and -independent pathways.

Jenkins Stephen John SJ Hewitson James Philip JP Ferret-Bernard Stephanie S Mountford Adrian Paul AP

International immunology 20050926 11

Exposure of the mammalian host to infective larvae of Schistosoma mansoni causes an acute inflammatory response in the skin and the activation of several cell types of the innate immune response including macrophages. Using an in vitro model of macrophage activation, we show that schistosome larvae possess molecules that directly stimulate both thioglycollate-elicited macrophages (tM) and IFNgamma-activated tM in vitro to produce several cytokines including IL-6, IL-12p40 and IL-10. The parasite ...[more]

PMID: 16186163

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Project description:BACKGROUND:Prothymosin ? (ProT?) (isoform 2: iso2) is a widely distributed, small acidic protein with intracellular and extracellular-associated functions. Recently, we identified two new ProT? variants with potent anti-HIV activity from CD8+ T cells and cervicovaginal lavage. The first is a splice variant of the ProT? gene known as isoB and the second is the product of ProT? pseudogene 7 (p7). Similarly to iso2, the anti-HIV activity of both variants is mediated by type I IFN. Here we tested whether the immunomodulatory activity of isoB and p7 are also TLR4 dependent and determined their kinetic of release in response to HIV-1 infection. METHODS:Type I, type III, TNF-? and IL-6 mRNA inducing activity was determined in macrophages from wild type and TLR4 knockout mice treated with recombinant ProT? variants. Supernatants from mock and HIV infected cells were analyzed by mass spectrometry in positive and negative modes for the presence of ProT? variants. In silico structural and functional analysis of ProT? variants were performed. RESULTS:We show that both isoB and p7 upregulate IFN-?, IFN-?1, IL-6, TNF-? and RANTES mRNAs in primary human macrophages. The potent stimulation of IFN-? by the recombinant ProT? variants in human macrophages is dependent on the TLR4 pathway, whereas the induction of TNF-? and IL-6 may also occur independently of TLR4, suggesting the interaction of ProT? variants with other signaling molecules/receptors. In silico analyses confirmed that the novel isoB and p7 variants are intrinsically disordered proteins, which lack the NLS and mass spectrometry showed release of ProT? variants within minutes post HIV-1 infection. These features are consistent with the function of ProT? variants as damage associate molecular patterns (DAMPs). CONCLUSIONS:Our findings indicate that ProT? variants strongly inhibit viral replication mainly, but not exclusively, through TLR4 signaling and that they are released within minutes of viral infection suggesting that they may function as DAMPs.

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Schistosome larvae stimulate macrophage cytokine production through TLR4-dependent and -independent pathways.

Publications

Schistosome larvae stimulate macrophage cytokine production through TLR4-dependent and -independent pathways.

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