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

Eunchong Park, Ju Han Song, Myun Soo Kim, Su Ho Park, Tae Sung Kim

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)508-516
Number of pages9
JournalInternational Immunopharmacology
Volume40
DOIs
Publication statusPublished - 2016 Nov 1

Fingerprint

Sesquiterpenes
Lactones
Mitogen-Activated Protein Kinases
T-Lymphocytes
Helper-Inducer T-Lymphocytes
Cell Differentiation
costunolide
Immune System Diseases
Phytochemicals
Adaptive Immunity
Regulatory T-Lymphocytes
Autoimmune Diseases
Anti-Inflammatory Agents
Phosphorylation

Keywords

  • Anti-inflammation
  • Costunolide
  • ERK
  • p38
  • T cell differentiation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

Costunolide, a sesquiterpene lactone, inhibits the differentiation of pro-inflammatory CD4+ T cells through the modulation of mitogen-activated protein kinases. / Park, Eunchong; Song, Ju Han; Kim, Myun Soo; Park, Su Ho; Kim, Tae Sung.

In: International Immunopharmacology, Vol. 40, 01.11.2016, p. 508-516.

Research output: Contribution to journalArticle

@article{a4738d8f5f474224ab08a0bb47680b3a,
title = "Costunolide, a sesquiterpene lactone, inhibits the differentiation of pro-inflammatory CD4+ T cells through the modulation of mitogen-activated protein kinases",
abstract = "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.",
keywords = "Anti-inflammation, Costunolide, ERK, p38, T cell differentiation",
author = "Eunchong Park and Song, {Ju Han} and Kim, {Myun Soo} and Park, {Su Ho} and Kim, {Tae Sung}",
year = "2016",
month = "11",
day = "1",
doi = "10.1016/j.intimp.2016.10.006",
language = "English",
volume = "40",
pages = "508--516",
journal = "International Immunopharmacology",
issn = "1567-5769",
publisher = "Elsevier",

}

TY - JOUR

T1 - Costunolide, a sesquiterpene lactone, inhibits the differentiation of pro-inflammatory CD4+ T cells through the modulation of mitogen-activated protein kinases

AU - Park, Eunchong

AU - Song, Ju Han

AU - Kim, Myun Soo

AU - Park, Su Ho

AU - Kim, Tae Sung

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

KW - Anti-inflammation

KW - Costunolide

KW - ERK

KW - p38

KW - T cell differentiation

UR - http://www.scopus.com/inward/record.url?scp=84991759033&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84991759033&partnerID=8YFLogxK

U2 - 10.1016/j.intimp.2016.10.006

DO - 10.1016/j.intimp.2016.10.006

M3 - Article

VL - 40

SP - 508

EP - 516

JO - International Immunopharmacology

JF - International Immunopharmacology

SN - 1567-5769

ER -