Piperine Ameliorates Trimellitic Anhydride-Induced Atopic Dermatitis-Like Symptoms by Suppressing Th2-Mediated Immune Responses via Inhibition of STAT6 Phosphorylation

Molecules. 2020 May 7;25(9):2186. doi: 10.3390/molecules25092186.

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

  • Alkaloids / pharmacology*
  • Alkaloids / therapeutic use
  • Animals
  • Anti-Allergic Agents / pharmacology*
  • Anti-Allergic Agents / therapeutic use
  • Benzodioxoles / pharmacology*
  • Benzodioxoles / therapeutic use
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Cells, Cultured
  • Chemokine CCL26 / genetics
  • Chemokine CCL26 / metabolism
  • Dermatitis, Atopic / chemically induced
  • Dermatitis, Atopic / drug therapy*
  • Disease Models, Animal
  • Female
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism
  • Humans
  • Interleukin-1beta / metabolism
  • Interleukin-4 / metabolism
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Lymph Nodes / drug effects
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Phosphorylation
  • Phthalic Anhydrides / toxicity
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Polyunsaturated Alkamides / pharmacology*
  • Polyunsaturated Alkamides / therapeutic use
  • Receptors, CCR3 / genetics
  • Receptors, CCR3 / metabolism
  • STAT6 Transcription Factor / metabolism*
  • Signal Transduction / drug effects*
  • Signal Transduction / immunology
  • Th2 Cells / drug effects
  • Th2 Cells / immunology*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Alkaloids
  • Anti-Allergic Agents
  • Benzodioxoles
  • CCL26 protein, mouse
  • CCR3 protein, human
  • Chemokine CCL26
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Interleukin-1beta
  • Phthalic Anhydrides
  • Piperidines
  • Polyunsaturated Alkamides
  • Receptors, CCR3
  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Interleukin-4
  • trimellitic anhydride
  • piperine