Abstract
Atopic dermatitis (AD) is a common inflammatory skin disease predominately related to Type 2 helper T (Th2) immune responses. In this study, we investigated whether piperine is able to improve AD symptoms using a trimellitic anhydride (TMA)-induced AD-like mouse model. Topical treatment with piperine reduced ear swelling (ear thickness and epidermal thickness) induced by TMA exposure. Furthermore, piperine inhibited pro-inflammatory cytokines such as TNF-α and IL-1β in mouse ears, compared with the TMA-induced AD group. In measuring allergic immune responses in draining lymph nodes (dLNs), we found that IL-4 secretion, GATA3 mRNA level, and STAT6 phosphorylation were suppressed by piperine treatment. In an ex vivo study, piperine also inhibited the phosphorylation of STAT6 on the CD4+ T cells isolated from splenocytes of BALB/c mice, and piperine suppressed IL-4-induced CCL26 mRNA expression and STAT6 phosphorylation in human keratinocytes resulting in the inhibition of infiltration of CCR3+ cells into inflammatory lesions. These results demonstrate that piperine could ameliorate AD symptoms through suppression of Th2-mediated immune responses, including the STAT6/GATA3/IL-4 signaling pathway. Therefore, we suggest that piperine is an excellent candidate as an inhibitor of STAT6 and may help to improve AD symptoms.
Keywords:
CCR3; STAT6; Th2 immune response; atopic dermatitis; piperine.
MeSH terms
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Alkaloids / pharmacology*
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Alkaloids / therapeutic use
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Animals
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Anti-Allergic Agents / pharmacology*
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Anti-Allergic Agents / therapeutic use
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Benzodioxoles / pharmacology*
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Benzodioxoles / therapeutic use
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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Cells, Cultured
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Chemokine CCL26 / genetics
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Chemokine CCL26 / metabolism
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Dermatitis, Atopic / chemically induced
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Dermatitis, Atopic / drug therapy*
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Disease Models, Animal
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Female
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / metabolism
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Humans
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Interleukin-1beta / metabolism
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Interleukin-4 / metabolism
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Keratinocytes / drug effects
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Keratinocytes / metabolism
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Lymph Nodes / drug effects
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Lymph Nodes / immunology
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Lymph Nodes / metabolism
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Mice
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Mice, Inbred BALB C
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Phosphorylation
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Phthalic Anhydrides / toxicity
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Piperidines / pharmacology*
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Piperidines / therapeutic use
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Polyunsaturated Alkamides / pharmacology*
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Polyunsaturated Alkamides / therapeutic use
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Receptors, CCR3 / genetics
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Receptors, CCR3 / metabolism
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STAT6 Transcription Factor / metabolism*
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Signal Transduction / drug effects*
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Signal Transduction / immunology
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Th2 Cells / drug effects
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Th2 Cells / immunology*
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Alkaloids
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Anti-Allergic Agents
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Benzodioxoles
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CCL26 protein, mouse
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CCR3 protein, human
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Chemokine CCL26
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GATA3 Transcription Factor
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Gata3 protein, mouse
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Interleukin-1beta
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Phthalic Anhydrides
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Piperidines
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Polyunsaturated Alkamides
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Receptors, CCR3
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STAT6 Transcription Factor
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Stat6 protein, mouse
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Tumor Necrosis Factor-alpha
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Interleukin-4
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trimellitic anhydride
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piperine