Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787.

Details

Serval ID
serval:BIB_238A57E800AE
Type
Article: article from journal or magazin.
Collection
Publications
Title
Anti-inflammatory effects of a cyclosporine receptor-binding compound, D-43787.
Journal
Journal of Pharmacology and Experimental Therapeutics
Author(s)
Pahl A., Zhang M., Török K., Kuss H., Friedrich U., Magyar Z., Szekely J., Horvath K., Brune K., Szelenyi I.
ISSN
0022-3565 (Print)
ISSN-L
0022-3565
Publication state
Published
Issued date
2002
Peer-reviewed
Oui
Volume
301
Number
2
Pages
738-746
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
By virtue of its binding to cyclophilin, the cellular receptor for cyclosporine (CsA), we could identify a new compound D-43787 [N-[(1-tert-butyloxycarbonyl)-indolin-2-(S)-carbonyl]-indolin-2-(S)-carbonacid-[N-epsilon-benzyloxycarbonyl)-2-(S)-lysin methylester]-amide] exhibiting immunomodulating properties. It inhibited cell proliferation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA)/ionomycin and anti-CD3/CD28 with an IC(50) of 0.3 microM. The protein phosphatase calcineurin, which is the target of the CsA-cyclophilin complex, is not inhibited by D-43787. It inhibited T helper cell (Th) 2 cytokines interleukin (IL)-4, -5, and -13 more effectively than the Th1 cytokine interferon (IFN)-gamma in human primary T cells. The IC(50) for IL-5 and IL-13 in TPA/ionomycin-stimulated peripheral blood mononuclear cells (PBMC) is 0.7 +/- 0.1 and 0.5 +/- 0.1 microM, respectively, whereas the IC(50) for IFN-gamma is 2.0 +/- 0.4 microM. When PBMC were stimulated with anti-CD3/CD28, the IC(50) for IL-4, -5, and -13 were 1.5 +/- 0.2, 1.8 +/- 0.2, and 1.9 +/- 0.4 microM, respectively. IFN-gamma was only partially inhibited under these conditions. This effect was even more pronounced in pure CD4(+) T cells. Pretreatment of human monocytes with D-43787 inhibited lipopolysaccharide-induced proinflammatory cytokines IL-6 and TNFalpha with an IC(50) of 1.2 +/- 0.1 and 4.7 +/- 0.9 microM, respectively. In vivo, D-43787 potently inhibited late-phase eosinophilia in actively sensitized and challenged guinea pigs (10 mg/kg, i.p.: 51%) and Brown-Norway rats (1 mg/kg, intrapulmonary: 66% 30 mg/kg, i.p.: 50%). In adjuvant-induced arthritis, D-43787 (10-40 mg/kg, b.i.d., i.p.) dose dependently reduced edema development on both hind paws. The potency of D-43787 was comparable with that of indomethacin and dexamethasone. In conclusion, we characterized a novel Th2 selective immunosuppressive drug with possible anti-asthmatic/anti-inflammatory effects. Its mode of action is distinct from that of CsA.
Keywords
Animals, Anti-Inflammatory Agents/pharmacology, Anti-Inflammatory Agents/therapeutic use, Arthritis, Experimental/drug therapy, Asthma/prevention & control, Cell Division/drug effects, Cyclophilin A/drug effects, Cyclophilin A/metabolism, Cyclosporine/pharmacology, Cytokines/metabolism, Disease Models, Animal, Dose-Response Relationship, Drug, Guinea Pigs, Humans, Immunosuppressive Agents/pharmacology, Immunosuppressive Agents/therapeutic use, Indoles/chemistry, Indoles/pharmacology, Injections, Intraperitoneal, Injections, Subcutaneous, Leukocytes, Mononuclear/cytology, Leukocytes, Mononuclear/drug effects, Lysine/analogs & derivatives, Lysine/chemistry, Male, Peptidylprolyl Isomerase/metabolism, Rats, Rats, Inbred BN, Rats, Inbred Lew, Th1 Cells/drug effects, Th1 Cells/metabolism, Th2 Cells/drug effects, Th2 Cells/metabolism
Pubmed
Web of science
Create date
08/10/2008 9:57
Last modification date
20/08/2019 13:01
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