title: Divergent actions by inhibitors of DP IV and APN family enzymes on CD4+ Teff cell motility and functions.
abstract: Dipeptidyl peptidase IV (DP IV)/CD26 and aminopeptidase N (APN)/CD13 family enzymes control T cell functions. We have previously defined these peptidases as targets to treat autoimmune disease, but the underlying mechanism is unclear. Here, we determined the effect of enzymatic inhibitors on chemotaxis by CD4+ effector T (Teff) cells. Exposure of Teff cells to the inhibitor of DP IV activity, Lys[Z(NO2)]-pyrrolidide (LZNP) and the inhibitor of APN activity, actinonin has no effect on chemotaxis or unstimulated cell migration, even at high inhibitor concentrations. LZNP and actinonin also fail to suppress migration of unfractionated lymph node cells, excluding paracrine action through other leukocyte subsets. In contrast, inhibition of DP IV and APN activities selectively suppresses lymphocyte functions including proliferation and production of the T helper type (Th)1 cytokine IFN-γ, the Th17 cytokine IL-17, as well as TNF-α, and ameliorates autoimmunity in vivo. The present results combined with previous studies suggest that LZNP and actinonin do not prevent migration of pathogenic Teff cells into target tissues, but rather suppress disease through inhibitor induced release of TGF-β by T cells at the site of inflammation.
authors.affiliation: Department of Pathology, Hebrew University Faculty of Medicine, 91120 Jerusalem, Israel.
authors.forename: Aliza
authors.initials: A
authors.lastname: Biton
authors.forename: Siegfried
authors.initials: S
authors.lastname: Ansorge
authors.forename: Ute
authors.initials: U
authors.lastname: Bank
authors.forename: Michael
authors.initials: M
authors.lastname: Täger
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
authors.forename: Stefan
authors.initials: S
authors.lastname: Brocke
mesh_terms: D000818:Animals; D018826:CD13 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy*; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D019076:Transgenes / Q000235:genetics
chemical_list: D054377:Chemokine CXCL12; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D011758:Pyrroles; D011759:Pyrrolidines; D013844:Thiazoles; D018826:CD13 Antigens; D018819:Dipeptidyl Peptidase 4; D008239:Lysine; C010531:actinonin