Agents and Actions

, Volume 22, Issue 1–2, pp 36–42 | Cite as

Histamine induced elevation of cyclic AMP phosphodiesterase activity in human monocytes

  • C. A. Holden
  • S. C. Chan
  • S. Norris
  • J. M. Hanifin
Histamine and Kinins


We have previously reported histamine desensitization of human blood mononuclear leukocytes resulting in reduced cAMP responses to β-adrenergic agonists, histamine and prostaglandin E1. This heterologous desensitization occurred at low, micromolar histamine concentrations and was accompanied by elevation of cAMP-phosphodiesterase (PDE) activity in these cells. We have now investigated the activity of PDE in the lymphocyte and monocyte fractions of mononuclear leukocytes to determine the site of histamine effect.

PDE activity per cell was higher in monocytes (0.075±0.070 units) than lymphocytes (0.026±0.08) units). Monocytes responded to 10−6M histamine stimulation with a much greater increase in PDE activity (0.354±0.1 units) than did lymphocytes (0.047±0.015 units). Histamine receptor studies, using thiazolylethylamine and chlorpheniramine as H1-agonist and antagonist respectively and dimaprit and cimetidine as H2-agonists and antagonists respectively, indicated that the histamine stimulation of PDE activity is mediated predominantly through H1 histamine receptor in the monocytes and the H2 receptor in the lymphocytes. Previously histamine had been thought to increase cyclic AMP by acting on H2 receptors to activate adenylate cyclase. Our studies show that stimulation of H1 or H2 receptors by low histamine concentration can cause the opposite effect i.e. increased catabolism and a net reduction in cAMP levels. The localization of this effect predominantly to monocytes indicates a potentially important mechanism for histamine action on immune regulation.


Histamine Cimetidine Histamine Receptor Chlorpheniramine Mononuclear Leukocyte 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    D. M. Chuang, J. K. William, L. Farber and E. Costa,Biochemical study of receptor internalization during β-adrenergic receptor desensitization in frog erythrocytes. Mol. Pharm.18, 348–355 (1980).Google Scholar
  2. [2]
    P. H. Scarpace and B. A. Itamar,Desensitization of adenylate cyclase and down regulation of beta adrenergic receptors after in vivo administration of beta agonist. J. Pharm. Exp. Ther.223, 327–331 (1982).Google Scholar
  3. [3]
    R. J. Lefkowitz, D. Mullikir and M. G. Caron,Regulation of β-adrenergic receptors by guanly-5'yl imidodiphosphate and other purine nucleotides. J. Biol. Chem.251, 4868–4692 (1976).Google Scholar
  4. [4]
    J. A. Beavo, R. S. Hansen, S. A. Harrison, R. L. Hurwitz, T. J. Martins and M. C. Mumby,Identification and properties of cyclic nucleotide phosphodiesterase. Mol. Cell. Endocrin.28, 387–410 (1982).CrossRefGoogle Scholar
  5. [5]
    W. J. Thompson, C. P. Ross, W. J. Pledger and S. J. Strada,Cyclic adenosine 3′, 5′-monophosphate phosphodiesterase: distinct forms in human lymphocytes and monocytes. J. Biol. Chem.251, 4922–4929 (1976).PubMedGoogle Scholar
  6. [6]
    J. H. Wedner, Y. C. Bruno, C. S. Parker and C. W. Parker,Cyclic nucleotide phosphodiesterase activity in human peripheral blood lymphocytes and monocytes. J. Immunol.123, 725–732 (1979).PubMedGoogle Scholar
  7. [7]
    S. C. Chan, S. R. Grewe, S. R. Stevens and J. M. Hanifin,Functional desensitization due to stimulation of cyclic AMP-phosphodiesterase in human mononuclear leukocytes. J. Cyclic Nucleotide Res.8, 211–224 (1982).PubMedGoogle Scholar
  8. [8]
    F. Gmelig-Meyling and N. Waldman,Separation of human blood monocytes and lymphocytes on a continuous percoll gradient. J. Immunol. Methods33, 1–9 (1980).CrossRefPubMedGoogle Scholar
  9. [9]
    N. A. Pawlowski, G. Kaplan, A. L. Hamill, L. A. Cohn and W. Scott,Arachidonic acid metabolism by human monocytes: Studies with platelet depleted culture. J. Exp. Med.158, 393–412 (1983).CrossRefPubMedGoogle Scholar
  10. [10]
    L. T. Yam, C. Y. Li and W. H. Crosby,Cytochemical identification of monocytes and granulocytes. Amer. J. Clin. Path.55, 283–290 (1971).Google Scholar
  11. [11]
    W. J. Thompson, W. L. Terasaki, P. M. Epstein and S. J. Strada,Assay of cyclic nucleotide phosphodiesterase and resolution of multiple forms of the enzyme. Adv. Cyclic Nucleotide Res.10, 69–82 (1980).Google Scholar
  12. [12]
    J. P. Moore, G. A. Smith, R. Hesketh and J. C. Metcalfe,Large effects of preparative techniques on lymphocyte cyclic AMP content. Biochem. J.216, 207–213 (1983).PubMedGoogle Scholar
  13. [13]
    S. M. Matloff, I. K. Kiselis and R. E. Rocklin,Reduced production of histamine induced suppressor factor (HSF) by atopic mononuclear cells and decreased prostaglandin E output by HSF-stimulated atopic monocytes. J. Allergy Clin. Immunol.72, 359–364 (1983).CrossRefPubMedGoogle Scholar
  14. [14]
    T. A. Guistina, S. C. Chan, J. W. Baker and J. M. Hanifin,Increased leukocyte sensitivity to PDE inhibitors in atopic dermatitis. J. Allergy Clin. Invest.74, 252–257 (1984).CrossRefGoogle Scholar
  15. [15]
    S. C. Chan, D. Trask, S. Shermann and J. M. Hanifin,Protein kinase C phosphorylation of a membrane precursor may account for increased cyclic AMP phosphodiesterase activity in atopic dermatitis monocytes. J. Invest. Dermatol. (1986) in press.Google Scholar
  16. [16]
    H. R. Bourne, G. M. Tomkins and A. Dion,Regulation of phosphodiesterase synthesis: requirement for cyclic adenosine monophosphate-dependent protein kinase. Science181, 952–954 (1973).PubMedGoogle Scholar
  17. [17]
    D. R. Bristow, J. R. Hare Jr., J. R. Hearn and L. E. Martin,Radioligand binding studies using (3 H)-cimetidine and (3 H)-ranitidine. Br. J. Pharmacol.72, 547 (1981).Google Scholar
  18. [18]
    D. B. Norris, T. J. Rising, S. E. Warrander and T. P. Wood, (3H)-cimetidine binding in guinea pig gastric mucosa. Br. J. Pharmacol.72, 548 (1981).Google Scholar

Copyright information

© Birkhäuser Verlag 1987

Authors and Affiliations

  • C. A. Holden
    • 1
  • S. C. Chan
    • 2
  • S. Norris
    • 2
  • J. M. Hanifin
    • 2
  1. 1.Department of DermatologySt. Helier HospitalCarshaltonEngland
  2. 2.Department of DermatologyOregon Health Sciences UniversityPortland

Personalised recommendations