TY - JOUR
T1 - Induction of dendritic cell maturation by pertussis toxin and its B subunit differentially initiate Toll-like receptor 4-dependent signal transduction pathways
AU - Wang, Zhao Yuan
AU - Yang, De
AU - Chen, Qian
AU - Leifer, Cindy A.
AU - Segal, David M.
AU - Su, Shao Bo
AU - Caspi, Rachel R.
AU - Howard, Zack O.M.
AU - Oppenheim, Joost J.
N1 - Funding Information:
Dr. Zhao Yuan Wang was supported by funds provided by Abgenics Inc. We are also grateful for the critical review of the manuscript by Dr. Igal Gery (NEI, NIH).
Funding Information:
This project was funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. The publisher or recipient acknowledges the right of the U.S. government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.
PY - 2006/8
Y1 - 2006/8
N2 - 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-κB 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-α, 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-κB 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.
AB - 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-κB 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-α, 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-κB 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.
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U2 - 10.1016/j.exphem.2006.04.025
DO - 10.1016/j.exphem.2006.04.025
M3 - Article
C2 - 16863919
AN - SCOPUS:33746035677
SN - 0301-472X
VL - 34
SP - 1115
EP - 1124
JO - Experimental Hematology
JF - Experimental Hematology
IS - 8
ER -