LPS-induced cytokine production in human dendritic cells is regulated by sialidase activity.
Removal of sialic acid from glycoconjugates on the surface of monocytes enhances their response to bacterial LPS. We tested the hypothesis that endogenous sialidase activity creates a permissive state for LPS-induced cytokine production in human monocyte-derived DCs. Of the four genetically distinct sialidases (Neu1-4), Neu1, Neu3, and Neu4 are expressed in human monocytes, but only Neu1 and Neu3 are up-regulated as cells differentiate into DCs. Neu1 and Neu3 are present on the surface of monocytes and DCs and are also present intracellularly. DCs contain a greater amount of sialic acid than monocytes, but the amount of sialic acid/mg total protein declines during differentiation to DCs. This relative hyposialylation of cells does not occur in mature DCs grown in the presence of zanamivir, a pharmacologic inhibitor of Neu3 but not Neu1, or DANA, an inhibitor of Neu1 and Neu3. Inhibition of sialidase activity during differentiation to DCs causes no detectable change in cell viability or expression of DC surface markers. Differentiation of monocytes into DCs in the presence of zanamivir results in reduced LPS- induced expression of IL-6, IL-12p40, and TNF-α by mature DCs, demonstrating a role for Neu3 in cytokine production. A role for Neu3 is supported by inhibition of cytokine production by DANA in DCs from Neu1⁻/⁻ and WT mice. We conclude that sialidase-mediated change in sialic acid content of specific cell surface glycoconjugates in DCs regulates LPS-induced cytokine production, thereby contributing to development of adaptive immune responses.
Stamatos
Nicholas M
NM
University of Maryland Medical Center, 725 West Lombard St., Baltimore, MD 21201, USA. nstamatos@ihv.umaryland.edu
Carubelli
Ivan
I
van de Vlekkert
Diantha
D
Bonten
Erik J
EJ
Papini
Nadia
N
Feng
Chiguang
C
Venerando
Bruno
B
d'Azzo
Alessandra
A
Cross
Alan S
AS
Wang
Lai-Xi
LX
Gomatos
Peter J
PJ
D000818:Animals; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000276:immunology*; D005679:G(M3) Ganglioside / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D009000:Monocytes / Q000166:cytology; D019158:N-Acetylneuraminic Acid / Q000032:analysis; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology
D016207:Cytokines; D005679:G(M3) Ganglioside; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; C486385:NEU1 protein, human; C465436:Neu3 protein, human; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid
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