title: Attractin, a dipeptidyl peptidase IV/CD26-like enzyme, is expressed on human peripheral blood monocytes and potentially influences monocyte function.
abstract: The ectoenzyme dipeptidyl peptidase IV (DP IV; CD26) was shown to play a crucial role in T cell activation. Several compounds inhibiting DP IV-like activity are currently under investigation for the treatment of Type 2 diabetes, rheumatoid arthritis, colitis ulcerosa, psoriasis, multiple sclerosis, and other diseases. In the present study, we show that human peripheral blood monocytes express a DP IV-like enzyme activity, which could be inhibited completely by the synthetic DP IV inhibitor Lys[Z(NO(2))]-thiazolidide. DP IV immunoreactivity was not detectable on monocytes, and DP IV transcript levels of monocytes were near the detection limit of quantitative polymerase chain reaction. However, monocytes exhibit a strong mRNA expression of the multifunctional DP IV-like ectoenzyme attractin and were highly positive for attractin in flow cytometric analysis. Fluorescence microscopy clearly demonstrated that attractin is located on the cell surface of monocytes. Attractin immunoprecipitates hydrolyzed Gly-Pro-pNA, indicating that monocyte-expressed attractin possesses DP IV-like activity. Inhibitor kinetic studies with purified human plasma attractin revealed that Lys[Z(NO(2))]-thiazolidide not only inhibits DP IV but also attractin (50% inhibition concentration=8.45 x 10(-9) M). Studying the influence of this inhibitor on monocyte functions, we observed a clear reduction of cell adhesion to fibronectin-coated culture plates in the presence of Lys[Z(NO(2))]-thiazolidide. Moreover, this inhibitor significantly modulates the production of interleukin-1 (IL-1) receptor antagonist, IL-6, and transforming growth factor-beta1 in lipopolysaccharide-stimulated monocyte cultures. In summary, here, we demonstrate for the first time expression of attractin on monocytes and provide first data suggesting that drugs directed to DP IV-like enzyme activity could affect monocyte function via attractin inhibition.
authors.affiliation: Institute of Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. sabine.wrenger@medizin.uni-magdeburg.de
authors.forename: Sabine
authors.initials: S
authors.lastname: Wrenger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Faust
authors.forename: Daniel
authors.initials: D
authors.lastname: Friedrich
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoffmann
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.forename: Uwe
authors.initials: U
authors.lastname: Lendeckel
authors.forename: Thilo
authors.initials: T
authors.lastname: Kähne
authors.forename: Anja
authors.initials: A
authors.lastname: Thielitz
authors.forename: Klaus
authors.initials: K
authors.lastname: Neubert
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009000:Monocytes / Q000201:enzymology* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C492192:ATRN protein, human; D006023:Glycoproteins; D008565:Membrane Proteins; D013844:Thiazoles; C093632:lysyl-(Z(nitro))thiazolidide; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase; D008239:Lysine