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-ε-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 IC50 of 0.3 μM. 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)-γ in human primary T cells. The IC50 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 μM, respectively, whereas the IC50 for IFN-γ is 2.0 ± 0.4 μM. When PBMC were stimulated with anti-CD3/CD28, the IC50 for IL-4, -5, and -13 were 1.5 ± 0.2, 1.8 ± 0.2, and 1.9 ± 0.4 μM, respectively. IFN-γ 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 TNFα with an IC50 of 1.2 ± 0.1 and 4.7 ± 0.9 μM, 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.
Footnotes
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This work was supported by the German Federal Ministry of Education and Research (Grant 0312231).
- Abbreviations:
- AIA
- adjuvans-induced arthritis
- BAL
- bronchoalveolar lavage
- BN
- brown Norway
- CsA
- cyclosporine
- GC
- glucocorticoid
- IFN
- interferon
- IL
- interleukin
- LPS
- lipopolysaccharide
- OVA
- ovalbumin
- PBMC
- peripheral blood mononuclear cells
- Th
- T helper cell
- TNF
- tumor necrosis factor
- TPA
- 12-O-tetradecanoylphorbol-13-acetate
- Received October 30, 2001.
- Accepted January 29, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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