Skip to main content
SpringerLink
Log in

Inhibition by anti-inflammatory drugs of prostaglandin production in cultured macrophages

Factors influencing the apparent drug effects

  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Summary

  1. 1.

    A sensitive, simple, reproducible, and economical assay for structure-activity investigations of non-steroidal anti-inflammatory drugs (NSAID) is lacking. This has promted us to investigate the advantages and limitations of defining for that purpose the potency of NSAID's as inhibitors of tumour promoter-induced prostaglandin (PG) release from mouse peritoneal macrophages in culture.

  2. 2.

    These cells release mainly PGE2 and PGI2 (measured as its stable hydrolysis product 6-keto-PGF1α) upon stimulation with the tumour promoter 12-O-tetradecanoylphorbol-13-acetate (TPA).

  3. 3.

    The PG release was dose-dependently inhibited by a variety of NSAID's. Their inhibitory potency was dependent on the culture conditions employed. The widely used acidic NSAID's were more potent when assayed under serum free culture conditions at low pH.

  4. 4.

    Dose response curves for acidic NSAID tested under serum free conditions allowed for the definition of IC50 values being reproducible within their 95% confidence limits.

  5. 5.

    The IC50 values obtained for different standard acidic NSAID's varied within 4 orders of magnitude. They corresponded favourably to their clinical potency and their potency in a variety of standard tests for antiinflammatory drugs.

  6. 6.

    IC50 values of five congeners of indomethacin differed up to 2 orders of magnitude in agreement with in vivo observations indicating the applicability of this assay for structure-activity investigations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bergmann ED, Pullman B (1974) Molecular and quantum pharmacology. D. Reidel Publishing Comp., Dordrecht

    Google Scholar 

  • Billingham ME, Davies GE (1979) Experimental models of arthritis in animals as screening test for drugs to treat arthritis in man. In: Vane, JR, Ferreira SH (eds) Handbook of experimental pharmacology, vol 50/II. Springer, Berlin Heidelberg New York, pp 108–135

    Google Scholar 

  • Bonney RJ, Wightman PD, Davies P, Sodowski SJ, Kuehl FA, Humes JL (1978) Regulation of prostaglandin synthesis and the selective release of lysosomal hydrolases by mouse peritoneal macrophages. Biochem J 176:433–442

    Google Scholar 

  • Bray MA, Gordon D (1978) Prostaglandin production by macrophages and the effect of anti-inflammatory drugs. Br J Pharmacol 63:635–642

    Google Scholar 

  • Brune K, Graf P (1978) Non-steroid anti-inflammatory drugs: Influence of extracellular pH on biodistribution and pharmacological effects. Biochem Pharmacol 27:525–530

    Google Scholar 

  • Brune K, Rainsford KD (1979) Prostaglandin release from macrophages: modulation by anti-inflammatory drugs. In: Rainsford KD, Ford-Hutchinson AW (eds) Prostaglandins and inflammation, Agents and Actions, Suppl 6. Birkhäuser, Basel, pp 159–165

    Google Scholar 

  • Brune K, Glatt M, Graf P (1976) Mechanisms of action of anti-inflammatory drugs. Gen Pharmacol 7:27–33

    Google Scholar 

  • Brune K, Glatt M, Kälin H, Peskar BA (1978) Pharmacological control of prostaglandin and thromboxane release from macrophages. Nature 274:261–263

    Google Scholar 

  • Cummings NA, Nordby GL (1966) Measurement of synovial fluid pH in normal and arthritic knees. Arthritis and Rheum 9:47–56

    Google Scholar 

  • Cushman DW, Cheung HS (1976) Effect of substrate concentration on inhibition of prostaglandin synthetase of bull seminal vesicles by anti-inflammatory drugs and fenamic acid analogs. Biochem Biophys Acta 424:449–459

    Google Scholar 

  • Glatt M, Kälin H, Wagner K, Brune K (1977) Prostaglandin release from macrophages: An assay system for anti-inflammatory drugs in vitro. Agents and Actions 7:321–326

    Google Scholar 

  • Goldstein A (1972) Biostatistics. New York: The MacMillan Comp. 1964

    Google Scholar 

  • Ham EA, Cirillo VJ, Zanetti M, Shen TY, Kuehl FA (1972) Studies on the mode of action of non-steroidal anti-inflammatory drugs. In: Ramwell PW, Phariss BB (eds) Prostaglandins in cellular biology. Plenum Press, New York, pp 345–352

    Google Scholar 

  • Humes JL, Bonney RJ, Pelus L, Dahlgren ME, Sadowski SJ, Kuehl FA, Davies P (1977) Macrophages sysnthesis and release prostaglandins in response to inflammatory stimuli. Nature 269:149–151

    Google Scholar 

  • Kurland JI, Bockman R (1978) Prostaglandin E production by human blood monocytes and mouse peritoneal macrophages. J Exp Med 147:952–957

    Google Scholar 

  • Moncada S, VAne JR (1980) Prostacyclin in the cardiovascular system. In: Samuelsson B, Ramwell PW, Paoletti R (eds) Advances in prostaglandin and thromboxane research, vol 6. Raven Press, New York, pp 43–60

    Google Scholar 

  • Morley J (1979) Prostaglandins and chronic inflammation. In: Rainsford KD, Ford-Hutchinson AW (eds) Prostaglandins and inflammation, Agents and Actions, Suppl 6. Birkhäuser, Basel, pp 133–142

    Google Scholar 

  • Peskar BA, Steffens Ch, Peskar BM (1979) Radioimmunoassay of 6-keto-prostaglandin F1α in biological material. In: Albertini A, Da Prada M, Peskar BA (eds) Radioimmunoassay of drugs and hormones in cardiovascular medicine. Elsevier, Amsterdam, pp 239–250

    Google Scholar 

  • Shen TY (1979) Prostaglandin synthetase inhibitors. In: Vane JR, Ferreira SH (eds) Handbook of experimental pharmacology, vol 50/II. Springer, Berlin, Heidelberg New York, pp 305–342

    Google Scholar 

  • Shen TY, Winter CA (1977) Chemical and biological studies on indomethacin, sulindac and their analogues. Adv Drug Res 12:89–245

    Google Scholar 

  • Sigmeth W, Placheta P (1978) Nicht-steroidale Antirheumatika. Z Allg Med 54:496–512

    Google Scholar 

  • Stone CA, Van Arman CG, Peck HM, Minsker DH, Ham EA (1974) Pharmacologic and toxicologic actions of prostaglandin synthetase inhibitors. Potential role of prostaglandin synthetase blockade. In: Robinson HJ, Vane JR (eds) Prostaglandin synthetase inhibitors. Raven Press, New York, pp 79–90

    Google Scholar 

  • Swingle KF (1974) Evaluation for anti-inflammatory activity. In: Sherrer FA, Whitehouse MW (eds) Anti-inflammatory agents. Medical chemistry, Vol 13/II. Academic Press, New York, pp 34–122

    Google Scholar 

  • Van Arman CG (1979) Oedema and increased vascular permeability. In: Vane JR, Ferreira SH (eds) Handbook of experimental pharmacology, Vol 50/II. Springer, Berlin, Heidelberg, New York, pp 75–91

    Google Scholar 

  • Weissmann G, Smolen JE, Korchak H (1980) Prostaglandins and inflammation: Receptor/cyclase coupling as an explanation of why PGEs and PGI2 inhibit functions of inflammatory cells. In: Samuelsson B, Ramwell PW, Paoletti R (eds) Advances in prostaglandin and thromboxane research, vol 8. Raven Press, New York, pp 1637–1653

    Google Scholar 

  • Winter CA, Nuss GW (1966) Treatment of adjuvant arthritis in rats with anti-inflammatory durgs. Arthritis Rheum 9:394–404

    Google Scholar 

  • Wong S, Gardocki JF, Pruss TP (1973) Pharmacologic evaluation of tolectin (Tolmetin®, McN-2559) and McN-2891, two anti-inflammatory agents. J Pharmacol Exp Ther 185:127–138

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Biozentrum, Pharmakologisches Institut, Klingelbergstrasse 70, CH4056, Basel, Switzerland

    Kay Brune, Kim D. Rainsford & Katharina Wagner

  2. Pharmakologisches Institut, Universität Freiburg, Hermann-Herder-Strasse 5, D-7800, Freiburg, Germany

    Bernhard A. Peskar

Authors
  1. Kay Brune
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kim D. Rainsford
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katharina Wagner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernhard A. Peskar
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brune, K., Rainsford, K.D., Wagner, K. et al. Inhibition by anti-inflammatory drugs of prostaglandin production in cultured macrophages. Naunyn-Schmiedeberg's Arch. Pharmacol. 315, 269–276 (1981). https://doi.org/10.1007/BF00499844

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00499844

Key words

Search

Navigation