A Helminth Glycan Induces APC Maturation via Alternative NF-κB Activation Independent of IκBα Degradation

Thomas, Paul G; Carter, Michele R; Da’dara, Akram A; DeSimone, Tiffany M; Harn, Donald A

doi:10.4049/jimmunol.175.4.2082

Cited by 76NF-κB Signaling PathwaysImmune Response and InflammationImmunotherapy and Immune Responses

A Helminth Glycan Induces APC Maturation via Alternative NF-κB Activation Independent of IκBα Degradation

Thomas, Paul G, Carter, Michele R, Da’dara, Akram A, DeSimone, Tiffany M, Harn, Donald A·2005·The Journal of Immunology

DOI 10.4049/jimmunol.175.4.2082

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Abstract

Activation of APCs via TLRs leads to activation of NF-κB, a key transcription factor in cells of the immune system most often associated with induction of Th1-type and proinflammatory responses. The neoglycoconjugate lacto-N-fucopentaose III (12-25 molecules)-dextran (LNFPIII-Dex) activates dendritic cells (DCs) via TLR4, as does LPS. However, unlike LPS, LNFPIII-Dex-activated cells induce Th2-type CD4+ T cell responses. This observation led us to ask whether LNFPIII-activated APCs were differentially activating NF-κB, and if so, could this partly account for how DCs mature in response to these two different pathogen-associated molecular patterns (PAMPs). In this study, we show that LNFPIII-Dex stimulation of APCs induces rapid, but transient NF-κB translocation and activity in the nucleus, in comparison with the persistent activation induced by LPS. We then demonstrate that transient vs persistent NF-κB activation has important implications in the development of the APC phenotype, showing that the second wave of NF-κB translocation in response to LPS is required for production of the proinflammatory mediator NO. In contrast to LPS, LNFPIII-stimulated APCs that only transiently activate NF-κB do not induce degradation of the known IκB family members or production of NO. However, cells stimulated with LNFPIII rapidly accumulate p50, suggesting that an alternative p105 degradation-dependent mechanism is primarily responsible for NF-κB activation downstream of LNFPIII. Finally, we show that while NF-κB translocation in LNFPIII-stimulated APCs is transient, it is required for the development of the DC 2 phenotype, confirming a crucial and multifaceted role for NF-κB in innate immune responses.

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The LNFPIII motif, present in both S. mansoni and human milk, has similar DC-modulating effects as total SEA and can act as an adjuvant for a type 2 immune response.
“The LNFPIII (lactose-N-fucopentose III) motif, present in both on S. mansoni and in human milk, has similar DC-modulating effects as total SEA (Thomas et al., 2005) and can act as an adjuvant for a type 2 immune response”
From Modulation of Host Immunity by Helminths: The Expanding Repertoire of Parasite Effector Molecules (2018) · cites this paper as Thomas et al., 2005

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Maturation of Dendritic Cell 2 Phenotype by a Helminth Glycan Uses a Toll-Like Receptor 4-Dependent Mechanism
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RESEARCH ARTICLE A Neoglycoconjugate Containing the Human Milk Sugar LNFPIII Drives Anti-Inflammatory Activation of Antigen Presenting Cells in a CD14 Dependent Pathway
Tundup, S., Srivastava, L., Norberg, T., & Harn, D. A. (2016)
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Authors: Thomas, P. G., Carter, M. R., Da’dara, A. A., DeSimone, T. M., & Harn, D. A.
Affiliations: Harvard University (US)
ORCID: Thomas, Paul G
Da’dara, Akram A
Venue: The Journal of Immunology
Publisher: Oxford University Press (OUP)
Published: 2005-08
Volume: 175
Issue: 4
Pages: 2082-2090
ISSN: 0022-1767 (ISSN-L)
1550-6606
DOI: 10.4049/jimmunol.175.4.2082
OpenAlex: W1665471078
Cited by: 76
References: 36
Citations by year: 2025: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2018: 4 · 2016: 3 · 2015: 6 · 2014: 7 · 2013: 7 · 2012: 4
FWCI: 1.63
Type: journal article
Language: en
Open access: closed
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations: The Journal of Immunology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Allergy and Infectious Diseases (R01AI056484)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: lacto-N-fucopentaose III, dendritic cell maturation, NF-κB activation, IκBα degradation, TLR4, lipopolysaccharide, Th2 immune response, nitric oxide production, innate immunity, pathogen-associated molecular patterns
MeSH terms: NF-KappaB Inhibitor alpha, Amino Sugars, Animals, Antigen-Presenting Cells, Antigens, Helminth, Cell Differentiation, Cell Line, Cells, Cultured, Dendritic Cells, Dextrans, Female, Lipopolysaccharides, Mice, Inbred BALB C, Mice, Transgenic, Nitric Oxide, Polysaccharides, Schistosoma mansoni, NF-kappa B, Mice, Knockout, Coculture Techniques, I-kappa B Proteins, Mice, NF-kappa B p50 Subunit

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A Helminth Glycan Induces APC Maturation via Alternative NF-κB Activation Independent of IκBα Degradation

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