Abstract
The effects of PDE inhibitors on oxazolone-induced contact hypersensitivity (CS) were studied in mice. Rolipram, Ro 20-1724 and theophylline dose dependently inhibited CS but none caused >53% inhibition. ED30 values at 24 h before challenge for rolipram, Ro 20-1724 and theophylline were 2.1, 5.4 and 30.4 mg/kg, p.o., respectively. Milrinone and SKF 94836 at 30 mg/kg caused a small, but significant inhibition of 13% and 18%, respectively, although the inhibition (8%) caused by zaprinast was not significant. Betamethasone (10 mg/kg, p.o.) caused a marked inhibition (80%) as did indomethacin (65% at 5 mg/kg, p.o.). Rolipram and Ro 20-1724 inhibited proliferation of mouse lymphoblasts with IC50 values of 0.08 μM and 0.83 μM, respectively. In contrast, zaprinast caused only a weak inhibition (IC50 = 119 μM) of lymphocyte proliferation, whereas SKF 94836 and theophylline failed to cause any significant inhibition at 100 μM (26% and 2%, respectively). These findings suggest that PDE IV isozymes play a principal role in mediating CS by inhibiting lymphocyte activation.
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Selected References
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- Bos J. D., Kapsenberg M. L., Smitt J. H. Pathogenesis of atopic eczema. Lancet. 1994 May 28;343(8909):1338–1341. doi: 10.1016/s0140-6736(94)92473-2. [DOI] [PubMed] [Google Scholar]
- Cher D. J., Mosmann T. R. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol. 1987 Jun 1;138(11):3688–3694. [PubMed] [Google Scholar]
- Cooper K. D., Kang K., Chan S. C., Hanifin J. M. Phosphodiesterase inhibition by Ro 20-1724 reduces hyper-IgE synthesis by atopic dermatitis cells in vitro. J Invest Dermatol. 1985 Jun;84(6):477–482. doi: 10.1111/1523-1747.ep12272486. [DOI] [PubMed] [Google Scholar]
- Frossard N., Landry Y., Pauli G., Ruckstuhl M. Effects of cyclic AMP- and cyclic GMP- phosphodiesterase inhibitors on immunological release of histamine and on lung contraction. Br J Pharmacol. 1981 Aug;73(4):933–938. doi: 10.1111/j.1476-5381.1981.tb08748.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gocinski B. L., Tigelaar R. E. Roles of CD4+ and CD8+ T cells in murine contact sensitivity revealed by in vivo monoclonal antibody depletion. J Immunol. 1990 Jun 1;144(11):4121–4128. [PubMed] [Google Scholar]
- Kapsenberg M. L., Wierenga E. A., Bos J. D., Jansen H. M. Functional subsets of allergen-reactive human CD4+ T cells. Immunol Today. 1991 Nov;12(11):392–395. doi: 10.1016/0167-5699(91)90137-I. [DOI] [PubMed] [Google Scholar]
- Krause D. S., Deutsch C. Cyclic AMP directly inhibits IL-2 receptor expression in human T cells: expression of both p55 and p75 subunits is affected. J Immunol. 1991 Apr 1;146(7):2285–2296. [PubMed] [Google Scholar]
- Lagente V., Moodley I., Perrin S., Mottin G., Junien J. L. Effects of isozyme-selective phosphodiesterase inhibitors on eosinophil infiltration in the guinea-pig lung. Eur J Pharmacol. 1994 Apr 1;255(1-3):253–256. doi: 10.1016/0014-2999(94)90107-4. [DOI] [PubMed] [Google Scholar]
- Li S. H., Chan S. C., Toshitani A., Leung D. Y., Hanifin J. M. Synergistic effects of interleukin 4 and interferon-gamma on monocyte phosphodiesterase activity. J Invest Dermatol. 1992 Jul;99(1):65–70. doi: 10.1111/1523-1747.ep12611858. [DOI] [PubMed] [Google Scholar]
- Marcoz P., Prigent A. F., Lagarde M., Nemoz G. Modulation of rat thymocyte proliferative response through the inhibition of different cyclic nucleotide phosphodiesterase isoforms by means of selective inhibitors and cGMP-elevating agents. Mol Pharmacol. 1993 Nov;44(5):1027–1035. [PubMed] [Google Scholar]
- Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
- Muñoz E., Zubiaga A. M., Merrow M., Sauter N. P., Huber B. T. Cholera toxin discriminates between T helper 1 and 2 cells in T cell receptor-mediated activation: role of cAMP in T cell proliferation. J Exp Med. 1990 Jul 1;172(1):95–103. doi: 10.1084/jem.172.1.95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Robicsek S. A., Blanchard D. K., Djeu J. Y., Krzanowski J. J., Szentivanyi A., Polson J. B. Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes. Biochem Pharmacol. 1991 Jul 25;42(4):869–877. doi: 10.1016/0006-2952(91)90047-9. [DOI] [PubMed] [Google Scholar]
- Tamir A., Isakov N. Cyclic AMP inhibits phosphatidylinositol-coupled and -uncoupled mitogenic signals in T lymphocytes. Evidence that cAMP alters PKC-induced transcription regulation of members of the jun and fos family of genes. J Immunol. 1994 Apr 1;152(7):3391–3399. [PubMed] [Google Scholar]
- Thompson W. J. Cyclic nucleotide phosphodiesterases: pharmacology, biochemistry and function. Pharmacol Ther. 1991;51(1):13–33. doi: 10.1016/0163-7258(91)90039-o. [DOI] [PubMed] [Google Scholar]
- Valette L., Prigent A. F., Némoz G., Anker G., Macovschi O., Lagarde M. Concanavalin A stimulates the Rolipram-sensitive isoforms of cyclic nucleotide phosphodiesterase in rat thymic lymphocytes. Biochem Biophys Res Commun. 1990 Jun 29;169(3):864–872. doi: 10.1016/0006-291x(90)91973-v. [DOI] [PubMed] [Google Scholar]
