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

TY - JOUR

T1 - Schistosome larvae stimulate macrophage cytokine production through TLR4-dependent and -independent pathways

AU - Jenkins, Stephen John

AU - Hewitson, James Philip

AU - Ferret-Bernard, Stephanie

AU - Mountford, Adrian Paul

PY - 2005/11

Y1 - 2005/11

N2 - 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.

AB - 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.

KW - IL-6

KW - IL-10

KW - IL-12p40

KW - innate

KW - MyD88

KW - MANSONI EGG ANTIGENS

KW - TOLL-LIKE RECEPTORS

KW - DENDRITIC CELLS

KW - IMMUNE-RESPONSE

KW - FUCOSYLATED EPITOPES

KW - PROTECTIVE IMMUNITY

KW - ADAPTER PROTEIN

KW - LEWIS-X

KW - MICE

KW - SKIN

U2 - 10.1093/intimm/dxh319

DO - 10.1093/intimm/dxh319

M3 - Article

C2 - 16186163

SN - 0953-8178

VL - 17

SP - 1409

EP - 1418

JO - International immunology

JF - International immunology

IS - 11

ER -