Suppression of arthritis by the inhibitors of dipeptidyl peptidase IV.
Dipeptidyl peptidase IV (DP IV, CD26) is a serine exoprotease which selectively cleaves the penultimate proline residue of polypeptides. This enzyme is also expressed as a surface marker on activated T cells. In order to assess the relevance of DP IV in immunological disorders, we evaluated the in vivo effects of specific DP IV inhibitors using two arthritis models, one which was induced by collagen one by alkyldiamine. These animal models share several pathological features associated with rheumatoid arthritis. The transition state substrate analog of DP IV, (S)-Alanylpyrrolidine-boronic Acid (Ala-boroPro), suppressed hind paw swelling, which was associated with collagen-induced and alkyldiamine-induced arthritis. A competitive inhibitor of DP IV, Lys(Z(NO2))-thiazolidide and an irreversible inhibitor, Ala-Pro-nitrobenzoylhydroxylamine also suppressed alkyldiamine-induced arthritis dose-dependently. We also analyzed the pharmacological effects of Lys(Z(NO2))-thiazolidide on several immune responses in vitro, in order to determine its mode of action. This inhibitor suppressed mitogen-induced and antigen-induced proliferation of T cells. However, studies using splenic cells from DP IV deficient rats showed that the inhibition of lymphocyte proliferation was not exerted through the inhibition of DP IV.
Tanaka
S
S
Lead Generation Research Laboratory, Tanabe Seiyaku Co., LTD., Osaka, Japan.
Murakami
T
T
Horikawa
H
H
Sugiura
M
M
Kawashima
K
K
Sugita
T
T
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D003094:Collagen / Q000633:toxicity; D003959:Diamines / Q000633:toxicity; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use*; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006898:Hydroxylamines / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018448:Models, Immunological; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology*
D001897:Boronic Acids; D003959:Diamines; D004151:Dipeptides; D006898:Hydroxylamines; D007166:Immunosuppressive Agents; D015842:Serine Proteinase Inhibitors; D013844:Thiazoles; C107757:alanylpyrrolidine-boronic acid; C093632:lysyl-(Z(nitro))thiazolidide; C042891:N-alanylproline-O-(4-nitrobenzoyl)hydroxylamine; D003094:Collagen; D018819:Dipeptidyl Peptidase 4; D008239:Lysine; C006270:avridine