title: Pseudoephedrine inhibits T-cell activation by targeting NF-κB, NFAT and AP-1 signaling pathways.
abstract: Pseudoephedrine (PSE) is a stereoisomer of ephedrine that is commonly used as a nasal decongestant in combination with other anti-inflammatory drugs for the symptomatic treatment of some common pathologies such as common cold. Herein, we describe for the first time the effects of PSE on T-cell activation events. We found that PSE inhibits interleukin-2 (IL-2) and tumor necrosis factor (TNF) alpha-gene transcription in stimulated Jurkat cells, a human T-cell leukemia cell line. To further characterize the inhibitory mechanisms of PSE at the transcriptional level, we examined the transcriptional activities of nuclear factor kappa B (NF-κB), nuclear factor of activated T cells (NFAT), and activator protein-1 (AP-1) transcription factors and found that PSE inhibited NF-κB-dependent transcriptional activity without affecting either the phosphorylation, the degradation of the cytoplasmic NF-κB inhibitory protein, IκBα or the DNA-binding activity. However, phosphorylation of the p65/RelA subunit was clearly inhibited by PSE in stimulated cells. In addition, PSE inhibited the transcriptional activity of NFAT without interfering with the calcium-induced NFAT dephosphorylation event, which represents the major signaling pathway for its activation. NFAT cooperates with c-Jun, a compound of the AP-1 complex, to activate target genes, and we also found that PSE inhibited both JNK activation and AP-1 transcriptional activity. These findings provide new mechanistic insights into the potential immunomodulatory activities of PSE and highlight their potential in designing novel therapeutic strategies to manage inflammatory diseases.
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Freiburg, Germany. bernd.fiebich@uniklinik-freiburg.de
authors.forename: Bernd L
authors.initials: BL
authors.lastname: Fiebich
authors.forename: Juan A
authors.initials: JA
authors.lastname: Collado
authors.forename: Cristian
authors.initials: C
authors.lastname: Stratz
authors.forename: Christian
authors.initials: C
authors.lastname: Valina
authors.forename: Willibald
authors.initials: W
authors.lastname: Hochholzer
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.forename: Luz M
authors.initials: LM
authors.lastname: Bellido
mesh_terms: D001993:Bronchodilator Agents / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D054199:Pseudoephedrine / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001993:Bronchodilator Agents; C508594:IL2 protein, human; D007376:Interleukin-2; D050778:NFATC Transcription Factors; C498143:RELA protein, human; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D054199:Pseudoephedrine; D051550:I-kappa B Kinase