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The Journal of Immunology, 2005, 175: 2082-2090.
Copyright © 2005 by The American Association of Immunologists

A Helminth Glycan Induces APC Maturation via Alternative NF-{kappa}B Activation Independent of I{kappa}B{alpha} Degradation1

Paul G. Thomas2, Michele R. Carter, Akram A. Da’dara, Tiffany M. DeSimone and Donald A. Harn3

Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115

Activation of APCs via TLRs leads to activation of NF-{kappa}B, 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-{kappa}B, 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-{kappa}B translocation and activity in the nucleus, in comparison with the persistent activation induced by LPS. We then demonstrate that transient vs persistent NF-{kappa}B activation has important implications in the development of the APC phenotype, showing that the second wave of NF-{kappa}B 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-{kappa}B do not induce degradation of the known I{kappa}B 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-{kappa}B activation downstream of LNFPIII. Finally, we show that while NF-{kappa}B 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-{kappa}B in innate immune responses.




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Infect. Immun.Home page
J. J. Reece, M. C. Siracusa, and A. L. Scott
Innate Immune Responses to Lung-Stage Helminth Infection Induce Alternatively Activated Alveolar Macrophages
Infect. Immun., September 1, 2006; 74(9): 4970 - 4981.
[Abstract] [Full Text] [PDF]




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