| Helminth parasites, which colonize organ systems as diverse as the lymphatics, gastrointestinal tract, and vasculature, have evolved multiple immunomodulatory mechanisms to manipulate host immune responses. Examination of DCs exposed to soluble egg antigens (SEA) from the trematode Schistosoma mansoni suggested that compared with their ability to strongly respond to bacterial pathogens, DCs are largely non-responsive to SEA. Recent evidence indicates that helminths have direct anti-inflammatory effects on innate immune responses to Toll-like receptor (TLR) ligation by viral and bacterial products. Using DCs derived from murine bone marrow, we demonstrate that SEA modulates TLR-ligand DC activation, suppressing proinflammatory responses and augmenting production of the anti-inflammatory cytokine, IL-10. The receptor for the SEA component responsible for this effect has remained elusive is unknown. We show that the anti-inflammatory and Th2-inducing characteristics of SEA are MyD88-independent and require neither TLR2 nor TLR4. Moreover, the anti-inflammatory components of SEA do not bind DCs in a calcium-dependent manner, suggesting that classical C-type lectins are not essential for SEA activity.; The ability of SEA to suppress TLR-induced signaling and DC activation, yet augment TLR-induced IL-10 production, was contradictory. The molecular mechanisms that regulate TLR-induced IL-10 production are not well understood. Emerging data suggests an under-appreciated role for PI3K activity in TLR-stimulated cytokine production, which has been proposed to be via the effects of Akt activation on NF-kappaB and MAPK activity. However, downstream effects of PI3K activation not only include control of transcription factor activation but stimulation of translation through the regulation of mTOR. We dissected the TLR ligand-induced signaling cascade to examine the role of PI3K activation on LPS-induced IL-10 production and demonstrate PI3K promotes IL-10 production by inducing gene transcription, activating mTOR to promote translation, and by stabilizing IL-10 mRNA.; Though a SEA receptor remains unidentified, SEA suppresses very early events in TLR-ligand induced signaling, which may indicate that ligand-TLR interactions or recruitment of TLR adaptor proteins is affected by SEA. Moreover, greater understanding of IL-10 production opens the possibility SEA augments TLR-ligand induced IL-10 production occurs through a post-transcriptional mechanism. This work has provided insight into the immunomodulatory potential of helminth antigens and their interactions with DCs. |
