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.
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Eunchong
authors.initials: E
authors.lastname: Park
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Ju Han
authors.initials: JH
authors.lastname: Song
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Myun Soo
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Su-Ho
authors.initials: SH
authors.lastname: Park
authors.affiliation: Division of Life Sciences, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address: tskim@korea.ac.kr.
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Kim
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000098815:T-bet Transcription Factor; D007783:Lactones
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D050990:GATA3 Transcription Factor; D018836:Inflammation Mediators; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D012717:Sesquiterpenes; D020825:T-Box Domain Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D000098815:T-bet Transcription Factor; C494748:Gata3 protein, mouse; C002602:costunolide; D007783:Lactones
keywords: Anti-inflammation; Costunolide; ERK; T cell differentiation; p38