Supression of inflammatory responses by labdane-type diterpenoids
- Departamento de Farmacologia Facultad de Farmacia, Universidad Complutense, Plaza Ramon y Cajal s/n, 28040 Madrid (Spain)
- Instituto de Investigaciones Biomedicas Alberto Sols (CSIC-UAM), Arturo Duperier 4, 28029 Madrid (Spain)
- Instituto de Quimica Organica (CSIC), Juan de la Cierva 3, 28006 Madrid (Spain)
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernandez Almagro 3, 28029 Madrid (Spain)
A series of 11 labdane-type diterpenoids (1-11) with various patterns of substitution were tested for potential anti-inflammatory activity. Of these compounds, 4 and 11 were selected to evaluate their influence on targets relevant to the regulation of the inflammatory response. These diterpenoids reduced the production of nitric oxide (NO), prostaglandin E2, and tumor necrosis factor-{alpha} in LPS-activated RAW 264.7 macrophages, with IC50 in the range 1-10 {mu}M. Inhibition of these inflammatory mediators was related to inhibition of the expression of nitric oxide synthase-2 (NOS-2) and cyclooxygenase-2 (COX-2) at the transcriptional level, as determined by western-blot and RT-PCR. Examination of the effects of these diterpenoids on nuclear factor {kappa}B signaling showed that both compounds inhibit the phosphorylation of I{kappa}B{alpha} and I{kappa}B{beta}, preventing their degradation and the nuclear translocation of the NF-{kappa}B p65 subunit. Inhibition of IKK activity was also observed. These derivatives displayed significant anti-inflammatory activity in vivo, suppressing mouse ear edema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and inhibiting myeloperoxidase activity, an index of neutrophil infiltration. The anti-inflammatory effects of these labdane diterpenoids, together with their low cell toxicity, suggest potential therapeutic applications in the regulation of the inflammatory response.
- OSTI ID:
- 21140813
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 228, Issue 2; Other Information: DOI: 10.1016/j.taap.2007.12.006; PII: S0041-008X(07)00558-3; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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