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We have now investigated the molecular mechanisms underpinning such immunomodulation and show here that ES-62-mediated downregulation of protein kinase C-\u03b4 (PKC-\u03b4), a TLR4-associated signalling mediator required for full activation of LPS-driven pro-inflammatory responses, is associated with induction of a low level of autophagic flux, as evidenced by upregulation and trafficking of p62 and LC3 and their consequent autophagolysosomal degradation. By contrast, the classical TLR4 ligand LPS, strongly upregulates p62 and LC3 expression but under such canonical TLR4 signalling this upregulation appears to reflect a block in autophagic flux, with these elements predominantly degraded in a proteasomal manner. These data are consistent with autophagic flux acting to homeostatically suppress proinflammatory DC responses and indeed, blocking of PKC-\u03b4 degradation by the autophagolysosomal inhibitors, E64d plus pepstatin A, results in abrogation of the ES-62-mediated suppression of LPS-driven release of IL-6, IL-12p70 and TNF-\u03b1 by DCs. Thus, by harnessing this homeostatic regulatory mechanism, ES-62 can protect against aberrant inflammation, either to promote parasite survival or serendipitously, exhibit therapeutic potential in inflammatory disease.<\/jats:p>","DOI":"10.1038\/srep37276","type":"journal-article","created":{"date-parts":[[2016,11,21]],"date-time":"2016-11-21T10:26:29Z","timestamp":1479723989000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosomal degradation of TLR-transducers, as exemplified by PKC\u03b4"],"prefix":"10.1038","volume":"6","author":[{"given":"Russell J.","family":"Eason","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kara S.","family":"Bell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fraser A.","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Rodgers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A.","family":"Pineda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina N.","family":"Steiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamyaa","family":"Al-Riyami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Harnett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret M.","family":"Harnett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,21]]},"reference":[{"key":"BFsrep37276_CR1","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1038\/nm1654","volume":"13","author":"AJ Melendez","year":"2007","unstructured":"Melendez, A. 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