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Exp Hematol. 2006 Aug;34(8):1115-24.

Induction of dendritic cell maturation by pertussis toxin and its B subunit differentially initiate Toll-like receptor 4-dependent signal transduction pathways.

Author information

1
Intramural Basic Research Program, SAIC-Frederick, Inc, USA.

Abstract

OBJECTIVE:

Pertussis toxin (PT) has the capacity to activate dendritic cells (DCs) for the augmentation of cell-mediated immune responses. To investigate the mechanism(s) by which PT activates DCs, we investigated the effects of PT and its B-oligomer (PTB) on the maturation of human and mouse DCs and determined whether PT could act as a pathogen-associated molecular pattern to activate one of the Toll-like receptors (TLRs).

METHODS:

The effects of PT and PTB on the maturation of human and mouse DCs were analyzed in terms of surface marker expression, cytokine production, antigen-presenting capacity, and intracellular signaling. The participation of TLR4 in PT-induced signaling was determined by comparing the effect of PT on DCs derived from TLR4-deficient and wild-type mice, as well as by measuring PT-induced NF-kappaB activation in HEK293 cells transiently transfected to express various TLRs.

RESULTS:

Although both promoted phenotypic and functional maturation DCs, however, unlike PT that induced DC production of interleukin (IL)-6, tumor necrosis factor-alpha, IL-12, and interferon-inducible protein, PTB was capable of stimulating the production of interferon-inducible protein. Bone marrow-derived DCs from C3H/HeJ mice with defective TLR-4 alleles were unresponsive to PT and PTB, whereas DCs from C3H/HeN mice responded. In addition, PT induced NF-kappaB activation and IL-8 production in HEK293 cells transfected with a combination of TLR4 and MD2 but not in nontransfected or TLR2-transfected HEK293 cells. Comparison of the patterns of cytokine induction and intracellular signaling events in DCs treated by PT and PTB revealed that although PT, like lipopolysaccharide, triggered both MyD88-dependent and -independent pathways, PTB preferentially triggered MyD88-independent pathways. Interestingly, mouse splenocyte proliferation in response to PT and PTB was only partially dependent on TLR4.

CONCLUSION:

The data identify PT as another pathogen-associated molecular pattern that induces DC maturation in a TLR4-dependent manner. Unlike PT, which triggers both MyD88-dependent and -independent pathways, PTB only triggers the MyD88-independent pathway in DCs.

PMID:
16863919
DOI:
10.1016/j.exphem.2006.04.025
[Indexed for MEDLINE]

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