title: Down-regulation of T cell activation following inhibition of dipeptidyl peptidase IV/CD26 by the N-terminal part of the thromboxane A2 receptor.
abstract: Using synthetic inhibitors, it has been shown that the ectopeptidase dipeptidyl peptidase IV (DP IV) (CD26) plays an important role in the activation and proliferation of T lymphocytes. The human immunodeficiency virus-1 Tat protein, as well as the N-terminal nonapeptide Tat(1-9) and other peptides containing the N-terminal sequence XXP, also inhibit DP IV and therefore T cell activation. Studying the effect of amino acid exchanges in the N-terminal three positions of the Tat(1-9) sequence, we found that tryptophan in position 2 strongly improves DP IV inhibition. NMR spectroscopy and molecular modeling show that the effect of Trp(2)-Tat(1-9) could not be explained by significant alterations in the backbone structure and suggest that tryptophan enters favorable interactions with DP IV. Data base searches revealed the thromboxane A2 receptor (TXA2-R) as a membrane protein extracellularly exposing N-terminal MWP. TXA2-R is expressed within the immune system on antigen-presenting cells, namely monocytes. The N-terminal nonapeptide of TXA2-R, TXA2-R(1-9), inhibits DP IV and DNA synthesis and IL-2 production of tetanus toxoid-stimulated peripheral blood mononuclear cells. Moreover, TXA2-R(1-9) induces the production of the immunosuppressive cytokine transforming growth factor-beta1. These data suggest that the N-terminal part of TXA2-R is an endogenous inhibitory ligand of DP IV and may modulate T cell activation via DP IV/CD26 inhibition.
authors.affiliation: Institute of Experimental Internal Medicine, Department of Internal Medicine, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany. sabine.wrenger@medizin.uni-magdeburg.de
authors.forename: S
authors.initials: S
authors.lastname: Wrenger
authors.forename: J
authors.initials: J
authors.lastname: Faust
authors.forename: C
authors.initials: C
authors.lastname: Mrestani-Klaus
authors.forename: A
authors.initials: A
authors.lastname: Fengler
authors.forename: A
authors.initials: A
authors.lastname: Stockel-Maschek
authors.forename: S
authors.initials: S
authors.lastname: Lorey
authors.forename: T
authors.initials: T
authors.lastname: Kahne
authors.forename: W
authors.initials: W
authors.lastname: Brandt
authors.forename: K
authors.initials: K
authors.lastname: Neubert
authors.forename: S
authors.initials: S
authors.lastname: Ansorge
authors.forename: D
authors.initials: D
authors.lastname: Reinhold
mesh_terms: D018819:Dipeptidyl Peptidase 4 / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D015696:Gene Products, tat / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation; D017482:Receptors, Thromboxane / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D015696:Gene Products, tat; D008024:Ligands; D017482:Receptors, Thromboxane; D018819:Dipeptidyl Peptidase 4