Costunolide, a sesquiterpene lactone, inhibits the differentiation of pro-inflammatory CD4+ T cells through the modulation of mitogen-activated protein kinases

CD4+ T cell activation and adequate differentiation into effector T helper (Th) cells are crucial for mediating adaptive immune responses to cope with foreign pathogens. Despite the significant role of Th cells, excessive increases in their numbers result in inflammatory and autoimmune diseases. In...

Full description

Saved in:
Bibliographic Details
Published in:International immunopharmacology 2016-11, Vol.40, p.508-516
Main Authors: Park, Eunchong, Song, Ju Han, Kim, Myun Soo, Park, Su-Ho, Kim, Tae Sung
Format: Article
Language:English
Subjects:
Adaptive immunity
Animals
Anti-inflammation
Anti-inflammatory agents
Anti-Inflammatory Agents - pharmacology
Autoimmune diseases
CD4 antigen
CD4-Positive T-Lymphocytes - drug effects
CD4-Positive T-Lymphocytes - immunology
CD69 antigen
Cell activation
Cell differentiation
Cell Differentiation - drug effects
Cell Proliferation - drug effects
Cells, Cultured
Chemical compounds
Costunolide
Cytokines - metabolism
Differentiation (biology)
Effector cells
ERK
Extracellular signal-regulated kinase
Extracellular Signal-Regulated MAP Kinases - metabolism
GATA-3 protein
GATA3 Transcription Factor - genetics
GATA3 Transcription Factor - metabolism
Gene expression
Genes
Helper cells
Immune response
Immunological diseases
Inflammation Mediators - metabolism
Inhibitors
JNK protein
Kinases
Lymphocyte Activation - drug effects
Lymphocytes
Lymphocytes T
Mice
Mice, Inbred C57BL
Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics
Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism
p38
p38 Mitogen-Activated Protein Kinases - metabolism
Pharmacology
Phosphorylation
Plants
Sesquiterpenes - pharmacology
Signal Transduction - drug effects
Stimulation
T cell differentiation
T cell receptors
T-Box Domain Proteins - genetics
T-Box Domain Proteins - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:CD4+ T cell activation and adequate differentiation into effector T helper (Th) cells are crucial for mediating adaptive immune responses to cope with foreign pathogens. Despite the significant role of Th cells, excessive increases in their numbers result in inflammatory and autoimmune diseases. In this study, we investigated the effects of costunolide, a plant-derived natural compound with an anti-inflammatory activity, in regulating Th cells and the underlying mechanisms. Costunolide significantly decreased cell populations of differentiated Th1, Th2, and Th17 subsets under Th subset-polarizing conditions, while exerting statistically negligible effects on Treg cell differentiation. Furthermore, costunolide inhibited the expression level of Th subset-polarizing master genes such as T-bet, GATA3, and RORγt, indicating that costunolide inhibits the differentiation of CD4+ T cells into Th subsets. Additionally, costunolide suppressed the proliferative activity of CD4+ T cells and the expression of CD69 activation marker on CD4+ T cells. When the molecular targets of costunolide were investigated, phosphorylation of ERK and p38 was found to be decreased under Th subset-polarizing conditions, whereas activity of JNK remained unchanged. U0126, an ERK inhibitor, and SB203580, a p38 inhibitor, decreased the expression of CD69 upon TCR stimulation and inhibited CD4+ T cell differentiation, indicating that both ERK and p38 are suggested to be critical molecular targets of costunolide. Taken together, these results suggest that costunolide inhibits the differentiation of CD4+ T cells by suppressing ERK and p38 activities and can be an effective therapeutic agent for T cell-mediated immune diseases. •Costunolide inhibits the differentiation of pro-inflammatory T helper cells.•Costunolide dampens the activation of CD4+ T cells upon TCR stimulation.•Costunolide is able to impede the proliferation of activated CD4+ T cells.•Molecular targets of costunolide in CD4+ T cells are ERK and p38.
ISSN:1567-5769
1878-1705
DOI:10.1016/j.intimp.2016.10.006