A helminth glycan induces APC maturation via alternative NF-kappa B activation independent of I kappa B alpha degradation.
Activation of APCs via TLRs leads to activation of NF-kappaB, 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-kappaB, 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-kappaB translocation and activity in the nucleus, in comparison with the persistent activation induced by LPS. We then demonstrate that transient vs persistent NF-kappaB activation has important implications in the development of the APC phenotype, showing that the second wave of NF-kappaB 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-kappaB do not induce degradation of the known IkappaB 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-kappaB activation downstream of LNFPIII. Finally, we show that while NF-kappaB 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-kappaB in innate immune responses.
Thomas
Paul G
PG
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Carter
Michele R
MR
Da'dara
Akram A
AA
DeSimone
Tiffany M
TM
Harn
Donald A
DA
D000606:Amino Sugars / Q000502:physiology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology* / Q000276:immunology* / Q000469:parasitology; D000947:Antigens, Helminth / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000469:parasitology; D003911:Dextrans / Q000494:pharmacology; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis; D011134:Polysaccharides / Q000502:physiology*; D012550:Schistosoma mansoni / Q000276:immunology
D000606:Amino Sugars; D000947:Antigens, Helminth; D003911:Dextrans; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C000606205:Nfkbia protein, mouse; D011134:Polysaccharides; C434666:lacto-N-fucopentaose III; D000072000:NF-KappaB Inhibitor alpha; C073701:Nfkb1 protein, mouse; D009569:Nitric Oxide