Wnt5a Promotes Inflammatory Responses via Nuclear Factor κB (NF-κB) and Mitogen-activated Protein Kinase (MAPK) Pathways in Human Dental Pulp Cells

Wnt5a has been found recently to be involved in inflammation regulation through a mechanism that remains unclear. Immunohistochemical staining of infected human dental pulp and tissue from experimental dental pulpitis in rats showed that Wnt5a levels were increased. In vitro, Wnt5a was increased 8-f...

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Bibliographic Details
Published in:The Journal of biological chemistry 2014-07, Vol.289 (30), p.21028-21039
Main Authors: Zhao, Yuan, Wang, Chen-Lin, Li, Rui-Min, Hui, Tian-Qian, Su, Ying-Ying, Yuan, Quan, Zhou, Xue-Dong, Ye, Ling
Format: Article
Language:English
Subjects:
Animals
Chemokine
Chemokine CCL2 - genetics
Chemokine CCL2 - metabolism
Cytokine
Dental Pulp - metabolism
Dental Pulp - pathology
Dental Pulp Cells
Female
Humans
Inflammation
Inflammation - genetics
Inflammation - metabolism
Inflammation - pathology
Inflammation Mediators - metabolism
Interleukin-1beta - genetics
Interleukin-1beta - metabolism
Interleukin-8 - genetics
Interleukin-8 - metabolism
Macrophages - metabolism
Macrophages - pathology
Male
MAP Kinase Signaling System
NF-kappa B - genetics
NF-kappa B - metabolism
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Rats
Rats, Wistar
Signal Transduction
Stromal Cell
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
Wnt Proteins - genetics
Wnt Proteins - metabolism
Wnt Signaling
Wnt-5a Protein
Wnt5a
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Summary:Wnt5a has been found recently to be involved in inflammation regulation through a mechanism that remains unclear. Immunohistochemical staining of infected human dental pulp and tissue from experimental dental pulpitis in rats showed that Wnt5a levels were increased. In vitro, Wnt5a was increased 8-fold in human dental pulp cells (HDPCs) after TNF-α stimulation compared with control cells. We then investigated the role of Wnt5a in HDPCs. In the presence of TNF-α, Wnt5a further increased the production of cytokines/chemokines, whereas Wnt5a knockdown markedly reduced cytokine/chemokine production induced by TNF-α. In addition, in HDPCs, Wnt5a efficiently induced cytokine/chemokine expression and, in particular, expression of IL-8 (14.5-fold) and CCL2 (25.5-fold), as assessed by a Luminex assay. The cytokine subsets regulated by Wnt5a overlap partially with those induced by TNF-α. However, no TNF-α and IL-1β was detected after Wnt5a treatment. We then found that Wnt5a alone and the supernatants of Wnt5a-treated HDPCs significantly increased macrophage migration, which supports a role for Wnt5a in macrophage recruitment and as an inflammatory mediator in human dental pulp inflammation. Finally, Wnt5a participates in dental pulp inflammation in a MAPK-dependent (p38-, JNK-, and ERK-dependent) and NF-κB-dependent manner. Our data suggest that Wnt5a, as an inflammatory mediator that drives the integration of cytokines and chemokines, acts downstream of TNF-α. Background: Wnt5a is involved in inflammation. Results: Wnt5a promotes an inflammatory response by up-regulating chemokines and cytokines via the NF-κB and MAPK pathways in HDPCs, leading to macrophage migration. Conclusion: Wnt5a, as an inflammatory mediator, drives the integration of cytokines and chemokines to control dental pulp inflammation. Significance: Wnt5a-mediated inflammation occurs downstream of TNF-α.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M113.546523