Differential effect of phosphodiesterase IV inhibitor RP73401 on various inflammatory and immune responses relevent to rheumatoid arthritis.
Phosphodiesterase (PDE) IV inhibitors have been reported to possess potent anti-inflammatory activities through enhancement of cAMP. In this study, the immunopharmacological effect of PDE IV inhibitor (RP73401) was further carefully evaluated. RP73401 strongly blocked the production of tumor necrosis factor (TNF)-alpha from lipopolysaccharide (LPS)-stimulated murine macrophages (RAW264.7) and human peripheral blood mononuclear cells (PBMC) and LPS-primed mice. RP73401 did not relieve joint inflammation in adjuvant-arthritis (RA) model, whereas the compound attenuated arachidonic acid-induced inflammation. RP73401 displayed weak or no modulatory effects on the activation of macrophage and lymphocytes (assessed by proliferation, nitric oxide (NO) release and cell-cell adhesion, TNF-alpha production upon phorbol 12-myristate 13-acetate (PMA) treatment), and fluorescein-isothiocynate (FITC)-induced ear oedema. Collectively, these data suggest that PDE IV inhibitor RP73401 may differentially modulate various immune responses and these may explain its inability to inhibit adjuvant-induced joint inflammation or FITC-induced ear oedema.
R&D Center, Daewoong Pharmaceutical Co. Ltd., Sungnam 462-120, South Korea. jaecho@kangwon.ac.kr
Jae Youl
JY
Cho
Joon Seok
JS
Park
Kyong Up
KU
Baik
June Goo
JG
Lee
Hyun Pyo
HP
Kim
Eun Sook
ES
Yoo
Myung Hwan
MH
Park
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D016718:Arachidonic Acid / Q000009:adverse effects / Q000037:antagonists & inhibitors; D001169:Arthritis, Experimental / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D001549:Benzamides / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D002468:Cell Physiological Phenomena / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004427:Ear Diseases / Q000139:chemically induced; D004487:Edema / Q000139:chemically induced; D006801:Humans; D007110:Immunity, Active / Q000187:drug effects* / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000037:antagonists & inhibitors; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009569:Nitric Oxide / Q000009:adverse effects / Q000378:metabolism; D011725:Pyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D020298:U937 Cells
D001549:Benzamides; D008070:Lipopolysaccharides; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D009569:Nitric Oxide; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D013755:Tetradecanoylphorbol Acetate; C087566:piclamilast