A salicylate-based small molecule HS-Cm exhibits immunomodulatory effects and inhibits dipeptidyl peptidase-IV activity in human T cells

Jun Ting Liou, Hsu Shan Huang, Meng Lin Chiang, Chin Sheng Lin, Shih Ping Yang, Ling Jun Ho, Jenn Haung Lai

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Activated T cells are key players in chronic inflammatory diseases, including atherosclerosis. Salicylates, like aspirin, display not only anti-inflammatory, anti-thrombotic, anti-atherosclerotic activities, but also immunomodulatory effects in T cells at high dosages. Here, we aimed to identify potent immunomodulators for T cells through cell-based screening from a mini-library of 300 salicylate-based small molecules, and elucidate the mechanisms. Human peripheral blood T cells were isolated from buffy coat. Phorbol 12-myristate 13-acetate plus ionomycin (P/I) was used to stimulate T cells. Cytokine production was measured by enzyme-linked immunosorbent assays. T cell activation markers were determined by flow cytometry. The activation of transcription factors and kinases was analyzed by western blotting, electrophoretic mobility shift assay, or kinase assay. Through library screening, we identified a small molecule named HS-Cm [C13H 9ClFNO2; N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide] that exhibited potent immunomodulatory effects on T cells with low cytotoxicity. In P/I-stimulated T cells, HS-Cm inhibited the production of interleukin-2, tumor necrosis factor-alpha, and interferon-gamma and suppressed the expression of surface activation markers CD25, CD69, and CD71, but not CD45RO. HS-Cm down-regulated DNA-binding activities of activator protein-1 and nuclear factor-kappa B, but not nuclear factor of activated T-cells, through inhibiting c-Jun N-terminal kinase/p38 and inhibitor of kappaB alpha (IκBα) kinase (IKK)/IκBα pathways, respectively. On the basis of structure-activity relationship, HS-Cm exerted considerable inhibition of dipeptidyl-peptidase IV/CD26 activity in T cells. Our results suggested that the small molecule HS-Cm exhibiting immunomodulatory effects on T cells may be useful for therapeutics in chronic inflammatory diseases, like atherosclerosis, diabetes and autoimmune arthritis.

Original languageEnglish
Pages (from-to)124-132
Number of pages9
JournalEuropean Journal of Pharmacology
Volume726
Issue number1
DOIs
Publication statusPublished - Mar 5 2014
Externally publishedYes

Fingerprint

Dipeptidyl Peptidase 4
Salicylates
Human Activities
T-Lymphocytes
Ionomycin
Phosphotransferases
Atherosclerosis
Chronic Disease
NFATC Transcription Factors
JNK Mitogen-Activated Protein Kinases
NF-kappa B
Transcription Factor AP-1
Immunologic Factors
Electrophoretic Mobility Shift Assay
Structure-Activity Relationship
Type 1 Diabetes Mellitus
Interferon-alpha
Aspirin
Interferon-gamma
Arthritis

Keywords

  • Arthritis
  • Atherosclerosis
  • Diabetes
  • Dipeptidyl-peptidase IV inhibitor
  • Salicylate
  • T lymphocyte

ASJC Scopus subject areas

  • Pharmacology
  • Medicine(all)

Cite this

A salicylate-based small molecule HS-Cm exhibits immunomodulatory effects and inhibits dipeptidyl peptidase-IV activity in human T cells. / Liou, Jun Ting; Huang, Hsu Shan; Chiang, Meng Lin; Lin, Chin Sheng; Yang, Shih Ping; Ho, Ling Jun; Lai, Jenn Haung.

In: European Journal of Pharmacology, Vol. 726, No. 1, 05.03.2014, p. 124-132.

Research output: Contribution to journalArticle

Liou, Jun Ting ; Huang, Hsu Shan ; Chiang, Meng Lin ; Lin, Chin Sheng ; Yang, Shih Ping ; Ho, Ling Jun ; Lai, Jenn Haung. / A salicylate-based small molecule HS-Cm exhibits immunomodulatory effects and inhibits dipeptidyl peptidase-IV activity in human T cells. In: European Journal of Pharmacology. 2014 ; Vol. 726, No. 1. pp. 124-132.
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AU - Yang, Shih Ping

AU - Ho, Ling Jun

AU - Lai, Jenn Haung

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