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. 1992;1(6):411–417. doi: 10.1155/S0962935192000620

Differential regulation of TNF-α and IL-1β production from endotoxin stimulated human monocytes by phosphodiesterase inhibitors

K L Molnar-Kimber 1,, L Yonno 1, R J Heaslip 1, B M Weichman 1
PMCID: PMC2365371  PMID: 18475493

Abstract

The effect of selective PDE-I (vinpocetine), PDE-III (milrinone, CI-930), PDE-IV (rolipram, nitroquazone), and PDE-V (zaprinast) isozyme inhibitors on TNF-α and IL-1β production from LPS stimulated human monocytes was investigated. The PDE-IV inhibitors caused a concentration dependent inhibition of TNF-α production, but only partially inhibited IL-1β at high concentrations. High concentrations of the PDE-III inhibitors weakly inhibited TNF-α, but had no effect on IL-1β production. PDE-V inhibition was associated with an augmentation of cytokine secretion. Studies with combinations of PDE isozyme inhibitors indicated that PDE-III and PDE-V inhibitors modulate rolipram's suppression of TNF production in an additive manner. These data confirm that TNF-α and IL-1β production from LPS stimulated human monocytes are differentially regulated, and suggest that PDE-IV inhibitors have the potential to suppress TNF levels in man.

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Selected References

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  1. Beavo J. A., Reifsnyder D. H. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci. 1990 Apr;11(4):150–155. doi: 10.1016/0165-6147(90)90066-H. [DOI] [PubMed] [Google Scholar]
  2. Beutler B., Cerami A. The biology of cachectin/TNF--a primary mediator of the host response. Annu Rev Immunol. 1989;7:625–655. doi: 10.1146/annurev.iy.07.040189.003205. [DOI] [PubMed] [Google Scholar]
  3. Brandwein S. R. Regulation of interleukin 1 production by mouse peritoneal macrophages. Effects of arachidonic acid metabolites, cyclic nucleotides, and interferons. J Biol Chem. 1986 Jul 5;261(19):8624–8632. [PubMed] [Google Scholar]
  4. Broide D. H., Lotz M., Cuomo A. J., Coburn D. A., Federman E. C., Wasserman S. I. Cytokines in symptomatic asthma airways. J Allergy Clin Immunol. 1992 May;89(5):958–967. doi: 10.1016/0091-6749(92)90218-q. [DOI] [PubMed] [Google Scholar]
  5. Burchett S. K., Weaver W. M., Westall J. A., Larsen A., Kronheim S., Wilson C. B. Regulation of tumor necrosis factor/cachectin and IL-1 secretion in human mononuclear phagocytes. J Immunol. 1988 May 15;140(10):3473–3481. [PubMed] [Google Scholar]
  6. Dinarello C. A. Interleukin-1 and interleukin-1 antagonism. Blood. 1991 Apr 15;77(8):1627–1652. [PubMed] [Google Scholar]
  7. Endres S., Fülle H. J., Sinha B., Stoll D., Dinarello C. A., Gerzer R., Weber P. C. Cyclic nucleotides differentially regulate the synthesis of tumour necrosis factor-alpha and interleukin-1 beta by human mononuclear cells. Immunology. 1991 Jan;72(1):56–60. [PMC free article] [PubMed] [Google Scholar]
  8. Endres S., Ghorbani R., Lonnemann G., van der Meer J. W., Dinarello C. A. Measurement of immunoreactive interleukin-1 beta from human mononuclear cells: optimization of recovery, intrasubject consistency, and comparison with interleukin-1 alpha and tumor necrosis factor. Clin Immunol Immunopathol. 1988 Dec;49(3):424–438. doi: 10.1016/0090-1229(88)90130-4. [DOI] [PubMed] [Google Scholar]
  9. Fenton M. J. Review: transcriptional and post-transcriptional regulation of interleukin 1 gene expression. Int J Immunopharmacol. 1992 Apr;14(3):401–411. doi: 10.1016/0192-0561(92)90170-p. [DOI] [PubMed] [Google Scholar]
  10. Fuller R. W., O'Malley G., Baker A. J., MacDermot J. Human alveolar macrophage activation: inhibition by forskolin but not beta-adrenoceptor stimulation or phosphodiesterase inhibition. Pulm Pharmacol. 1988;1(2):101–106. doi: 10.1016/s0952-0600(88)80006-1. [DOI] [PubMed] [Google Scholar]
  11. Giembycz M. A. Could isoenzyme-selective phosphodiesterase inhibitors render bronchodilator therapy redundant in the treatment of bronchial asthma? Biochem Pharmacol. 1992 May 28;43(10):2041–2051. doi: 10.1016/0006-2952(92)90160-k. [DOI] [PubMed] [Google Scholar]
  12. Hurme M. Modulation of interleukin-1 beta production by cyclic AMP in human monocytes. FEBS Lett. 1990 Apr 9;263(1):35–37. doi: 10.1016/0014-5793(90)80699-j. [DOI] [PubMed] [Google Scholar]
  13. Kassis S., Lee J. C., Hanna N. Effects of prostaglandins and cAMP levels on monocyte IL-1 production. Agents Actions. 1989 Jun;27(3-4):274–276. doi: 10.1007/BF01972795. [DOI] [PubMed] [Google Scholar]
  14. Knudsen P. J., Dinarello C. A., Strom T. B. Prostaglandins posttranscriptionally inhibit monocyte expression of interleukin 1 activity by increasing intracellular cyclic adenosine monophosphate. J Immunol. 1986 Nov 15;137(10):3189–3194. [PubMed] [Google Scholar]
  15. Komas N., Lugnier C., Andriantsitohaina R., Stoclet J. C. Characterisation of cyclic nucleotide phosphodiesterases from rat mesenteric artery. Eur J Pharmacol. 1991 Sep 12;208(1):85–87. doi: 10.1016/0922-4106(91)90056-n. [DOI] [PubMed] [Google Scholar]
  16. Kovacs E. J., Radzioch D., Young H. A., Varesio L. Differential inhibition of IL-1 and TNF-alpha mRNA expression by agents which block second messenger pathways in murine macrophages. J Immunol. 1988 Nov 1;141(9):3101–3105. [PubMed] [Google Scholar]
  17. Livi G. P., Kmetz P., McHale M. M., Cieslinski L. B., Sathe G. M., Taylor D. P., Davis R. L., Torphy T. J., Balcarek J. M. Cloning and expression of cDNA for a human low-Km, rolipram-sensitive cyclic AMP phosphodiesterase. Mol Cell Biol. 1990 Jun;10(6):2678–2686. doi: 10.1128/mcb.10.6.2678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  19. Nicholson C. D., Challiss R. A., Shahid M. Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol Sci. 1991 Jan;12(1):19–27. doi: 10.1016/0165-6147(91)90484-a. [DOI] [PubMed] [Google Scholar]
  20. Renz H., Gong J. H., Schmidt A., Nain M., Gemsa D. Release of tumor necrosis factor-alpha from macrophages. Enhancement and suppression are dose-dependently regulated by prostaglandin E2 and cyclic nucleotides. J Immunol. 1988 Oct 1;141(7):2388–2393. [PubMed] [Google Scholar]
  21. Rordorf-Adam C., Lazdins J., Woods-Cook K., Alteri E., Henn R., Geiger T., Feige U., Towbin H., Erard F. An assay for the detection of interleukin-1 synthesis inhibitors: effects of antirheumatic drugs. Drugs Exp Clin Res. 1989;15(8):355–362. [PubMed] [Google Scholar]
  22. Slungaard A., Vercellotti G. M., Walker G., Nelson R. D., Jacob H. S. Tumor necrosis factor alpha/cachectin stimulates eosinophil oxidant production and toxicity towards human endothelium. J Exp Med. 1990 Jun 1;171(6):2025–2041. doi: 10.1084/jem.171.6.2025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Strieter R. M., Remick D. G., Ward P. A., Spengler R. N., Lynch J. P., 3rd, Larrick J., Kunkel S. L. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Commun. 1988 Sep 30;155(3):1230–1236. doi: 10.1016/s0006-291x(88)81271-3. [DOI] [PubMed] [Google Scholar]
  24. Torphy T. J., Livi G. P., Balcarek J. M., White J. R., Chilton F. H., Undem B. J. Therapeutic potential of isozyme-selective phosphodiesterase inhibitors in the treatment of asthma. Adv Second Messenger Phosphoprotein Res. 1992;25:289–305. [PubMed] [Google Scholar]
  25. Wasik M. A., Beller D. I. Induction of macrophage membrane interleukin 1 expression by T-cell dependent and T-cell independent pathways is inhibited by cyclosporin A. Clin Immunol Immunopathol. 1989 Aug;52(2):331–340. doi: 10.1016/0090-1229(89)90184-0. [DOI] [PubMed] [Google Scholar]

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