Cyclic Nucleotides, Arachidonic Acid, and Polyamines in the Pathophysiology of Inflammatory Proliferative Skin Diseases

  • John J. Voorhees
Part of the Comprehensive Immunology book series (COMIMUN, volume 7)


Psoriasis is a multifactorial genetic disease (Watson et al., 1972) in which a major feature is an exaggerated epidermal proliferation. Various disorders in immunodermatology such as allergic contact dermatitis and atopic dermatitis have increases of normal epithelial proliferation as a major feature of the lesion. At least at the level of current understanding, there is reason to assume that many of the described abnormal mechanisms in psoriatic epithelium will also be present in hyperplastic epidermis in general. This chapter will cover mechanisms of proliferation, using psoriasis as a model, with the idea that the knowledge may well pertain to epidermis stimulated to proliferate by immune injury.


Arachidonic Acid Cyclic Nucleotide Psoriatic Lesion Free Arachidonic Acid Psoriatic Epidermis 
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  1. Anderson, W. B., and Jaworski, C. J., 1977, Modulation of adenylate cyclase activity of fibroblasts by free fatty acids and phospholipids, Arch. Biochem. Biophys. 180: 374–383.PubMedCrossRefGoogle Scholar
  2. Anonymous, 1976, Cyclic AMP and dibutyryl AMP in treatment of psoriasis, Chin. Med. J. 2: 141–146.Google Scholar
  3. Aso, K., Deneau, D. G., Krulig, L., Wilkinson, D. I., and Farber, E. M., 1975a, Epidermal synthesis of prosta-glandins and their effect on levels of cyclic adenosine 3’,5’-monophosphate, J. Invest. Dermatol. 64: 326–331.PubMedCrossRefGoogle Scholar
  4. Aso, K., Orenberg, E. K., and Farber, E. M., 1975b, Reduced epidermal cyclic AMP accumulation following prostaglandin stimulation: Its possible role in the pathophysiology of psoriasis, J. Invest. Dermatol. 65: 375–378.PubMedCrossRefGoogle Scholar
  5. Baig, M. M., and Roberts, R. M., 1973, Comparative studies on the carbohydrate-containing membrane components of normal and adenosine 3’:5’-cyclic monophosphate-treated chinese-hamster ovary cells, Biochem. J. 134: 329–339.PubMedGoogle Scholar
  6. Braun-Falco, O., 1958, The histochemistry of psoriasis, Ann. N.Y. Acad. Sci., 73: 936–976.PubMedGoogle Scholar
  7. Bullough, W. S., and Laurence, E. B., 1964, Mitotic control by internal secretion: The role of the chalone-adrenalin complex, Exp. Cell Res. 33: 176–194.PubMedCrossRefGoogle Scholar
  8. Carter, T. N., 1972, The relationship of lithium carbonate to psoriasis, Psychosomatics 13: 325–327.PubMedGoogle Scholar
  9. Chopra, D. P., 1977, Effects of theophylline and dibutyryl cyclic AMP on proliferation and keratinization of human keratinocytes, Br. J. Dermatol. 96: 255–262.PubMedCrossRefGoogle Scholar
  10. Cooper, R. A., 1977, Abnormalities of cell-membrane fluidity in the pathogenesis of disease, N. Engl. J. Med. 297 (7): 371–377.PubMedCrossRefGoogle Scholar
  11. Delescluse, C., Colburn, N. H., Duell, E. A., and Voorhees, J. J., 1974, Cyclic AMP-elevating agents inhibit proliferation of keratinizing guinea pig epidermal cells, Differentiation 2: 343–350.PubMedCrossRefGoogle Scholar
  12. Delescluse, C., Fukuyama, K., and Epstein, W. L., 1976, Dibutyryl cyclic AMP-induced differentiation of epidermal cells in tissue culture, J. Invest. Dermatol. 66: 8–13.CrossRefGoogle Scholar
  13. Emmelot, P., 1973, Biochemical properties of normal and neoplastic cell surfaces; a review, Eur. J. Cancer 9: 319–333.PubMedCrossRefGoogle Scholar
  14. Fillingame, R. H., Jorstad, C. M., and Morris, D. R., 1975, Increased cellular levels of spermidine or spermine are required for optimal DNA synthesis in lymphocytes activated by concanavalin A, Proc. Natl. Acad. Sci. USA 72: 4042–4045.PubMedCrossRefGoogle Scholar
  15. Flaxman, B. A., and Harper, R. A., 1975, In vitro analysis of the control of keratinocyte proliferation in human epidermis by physiologic and pharmacologic agents, J. Invest. Dermatol. 65: 52–59.Google Scholar
  16. Fraki, J. E., and Hopsu-Havu, V. K., 1976, Plasminogen activator and histone hydrolyzing proteases in psoriasis scales—Possible role in increased cell division, Ann. Clin. Res. 8: 335–339.PubMedGoogle Scholar
  17. Friedman, D. L., 1976, Role of cyclic nucleotides in cell growth and differentiation, Physiol. Rev. 56: 652–708.Google Scholar
  18. Goetzl, E. J., Woods, J. M., and Gorman, R. R., 1977, Stimulation of human eosinophil and neutrophil polymorphonuclear leukocyte chemotaxis and random migration by 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid, J. Clin, Invest. 59: 179–183.CrossRefGoogle Scholar
  19. Goldberg, N. D., and Haddox, M. K., 1977, Cyclic GMP metabolism and involvement in biological regulation, Annu. Rev. Biochem. 46: 823–896.PubMedCrossRefGoogle Scholar
  20. Goodwin, P., Hamilton, S., and Frey, L., 1973, A comparison between DNA synthesis and mitosis in unin-volved and involved psoriatic epidermis and normal epidermis, Br. J. Dermatol. 89: 613–618.PubMedCrossRefGoogle Scholar
  21. Hadden, J. W., Hadden, E. M., Haddox, M. K., and Goldberg, N. D., 1972, Guanosine 3’:5’-cyclic mono-phosphate: A possible intracellular mediator of mito-genic influences in lymphocytes, Proc. Natl. Acad. Sci. USA 69: 3024–3027.PubMedCrossRefGoogle Scholar
  22. Hammarström, S., Hamberg, M., Samuelsson, B., Duell, E. A., Stawiski, M., and Voorhees, J. J., 1975, Increased concentrations of nonesterified arachidonic acid, 12-L-hydroxy-5,8,10,14-eicosatetraenoic acid, prostaglandin E2 and prostaglandin F2ain epidermis of psoriasis, Proc. Natl. Acad. Sci. USA 72: 5130–5134.PubMedCrossRefGoogle Scholar
  23. Härkönen, M., Hopsu-Havu, V. K., and Raij, K., 1974, Cyclic adenosine monophosphate, adenyl cyclase and cyclic nucleotide phosphodiesterase in psoriatic epidermis, Acta Derm. Venereol. 54: 13–18.Google Scholar
  24. Hidaka, H., and Asano, T., 1977, Stimulation of human platelet guanylate cyclase by unsaturated fatty acid peroxides, Proc. Natl. Acad. Sci. USA 74: 3657–3661.PubMedCrossRefGoogle Scholar
  25. Insel, P. A., and Fenno, J., 1978, Cyclic AMP-dependent protein kinase mediates a cyclic AMP-stimulated decrease in ornithine and S-adenosyl-methionine decarboxylase activities, Proc. Natl. Acad. Sci. USA 75: 862–865.PubMedCrossRefGoogle Scholar
  26. Johnson, G. S., and Pastan, I., 1971, Change in growth and morphology of fibroblasts by prostaglandins, J. Natl. Cancer Inst. 47: 1357–1364.PubMedGoogle Scholar
  27. Kassis, V., Weismann, K., Heiligstädt, H., and Söndergaard, J., 1977, Synthesis of prostaglandins by psoriatic skin, Arch. Dermatol. Res. 259: 207–212.PubMedCrossRefGoogle Scholar
  28. Lapetina, E. G., Schmitges, C. J., Chandrabose, K., and Cuatrecasas, P., 1977, Cyclic adenosine 3’,5’-monophosphate and prostacyclin inhibit membrane phospholipase activity in platelets, Biochem. Biophys. Res. Commun. 76: 828–835.PubMedCrossRefGoogle Scholar
  29. Mahrle, G., and Orfanos, C. E., 1975, R-Adrenerge Stimulation membrangebundener Adenylcyklase in normaler Epidermis and mangelnde Stimulierbarkeit bei Psoriasis, Arch. Dermatol. Res. 253: 195–202.PubMedCrossRefGoogle Scholar
  30. Mahrle, G., and Orfanos, C. E., 1977, The plasma unit membrane, Br. J. Dermatol. 96: 215–223.PubMedCrossRefGoogle Scholar
  31. Mamont, P. S., Böhlen, P., McCann, P. P., Bey, P., Schuber, F., and Tardif, C., 1976, a-Methyl ornithine, a potent competitive inhibitor of ornithine decarboxylase, blocks proliferation of rat hepatoma cells in culture, Proc. Natl. Acad. Sci. USA 73: 1626–1630.Google Scholar
  32. Marcelo, C. L., Duell, E. A. and Voorhees, J. J., 1978, Cyclic nucleotide levels in psoriatic and normal populations, in: Advances in Cyclic Nucleotide Research ( W. George, L. Ignarro, G. A. Robison, and P. Greengard, eds.), Raven Press, New York.Google Scholar
  33. McMichael, A. J., Morhenn, V., Payne, R., Sasazuki, T., and Farber, E. M., 1978, HLA C and D antigens associated with psoriasis, Br. J. Dermatol. 98: 287–292.PubMedCrossRefGoogle Scholar
  34. Meruelo, D., and Edidin, M., 1975, Association of mouse liver adenosine 3’:5’-cyclic monophosphate (cyclic AMP) leveles with histocompatibility-2 genotype, Proc. Natl. Acad. Sci. USA 72: 2644–2648.PubMedCrossRefGoogle Scholar
  35. Minkes, M., Stanford, N., Chi, M. M.-Y., Roth, G. J., Raz, A., Needleman, P., and Majerus, P. W., 1977, Cyclic adenosine 3’,5’-monophosphate inhibits the availability of arachidonate to prostaglandin synthetase in human platelet suspensions, J. Clin. Invest. 59: 449–454.PubMedCrossRefGoogle Scholar
  36. Muller, W. E. G., Muller, I., Zahn, R. K., and Kurelec, B., 1978, Species-specific aggregation factor in sponges, Cell Tissue Kinet. 11: 23–32.PubMedGoogle Scholar
  37. Nesbitt, J. A., Anderson, W. B., Miller, Z., Pastan, I., Russell, T. R., and Gospodarowicz, D., 1976, Guanylate cyclase and cyclic guanosine 3’:4’-monophosphate phosphodiesterase activities and cyclic guanosine 3’:5’monophosphate levels in normal and transformed fibroblasts in culture, J. Biol. Chem. 251: 2344–2352.PubMedGoogle Scholar
  38. Newcombe, D. S., Ciosek, C. P., Jr., Ishikawa, Y., and Fahey, J. V., 1975, Human synoviocytes: Activation and desensitization by prostaglandins and l-epinephrine, Proc. Natl. Acad. Sci. USA 72: 3124–3128.PubMedCrossRefGoogle Scholar
  39. Penneys, N. S., Ziboh, V., Lord, J., and Simon, P., 1975, Ihibitor(s) of prostaglandin synthesis in psoriatic plaque, Nature (London) 254: 351–352.CrossRefGoogle Scholar
  40. Penneys, N. S., Simon, P., Ziboh, V. A., and Schlossberg, J., 1977, In vivo chemotaxis induced by polyunsaturated fatty acids, J. Invest. Dermatol. 69: 435–438.Google Scholar
  41. Posternak, F., Posternak, T., Orusco, M., Cehovic, G., and Laugier, P., 1976, Essais de traitement du psoriasis par injections intra-lésionnelles d’AMPc, de dibutyryl8-thin AMPc, et de théophylline, Journ. Nat. Dermatol. 103: 640–644.Google Scholar
  42. Puck, T. T., 1977, Cyclic AMP, the microtubule-microfilament system, and cancer, Proc. Natl. Acad. Sci. USA 74: 4491–4495.PubMedCrossRefGoogle Scholar
  43. Ramwell, P. W., Leovey, E. M. K., and Sintetos, A. L., 1977, Regulation of the arachidonic acid cascade, Biol. Reprod. 16: 70–87.PubMedCrossRefGoogle Scholar
  44. Russell, D. H., and Stambrook, P. J., 1975, Cell cycle specific fluctuations in adenosine 3’:5’-cyclic mono-phosphate and polyamines of chinese hamster cells, Proc. Natl. Acad. Sci. USA 72: 1482–1486.PubMedCrossRefGoogle Scholar
  45. Russell, D. H., Combest, W. L., Duell, E. A., Stawiski, M. A., Anderson, T. F., and Voorhees, J. J., 1978, Glucocorticoid inhibits elevated polyamine biosynthesis in psoriasis, J. Invest. Dermatol. 71: 177–181.PubMedCrossRefGoogle Scholar
  46. Schmidt, C., Penneys, N. S., Ziboh, V. A., Kiem, I., and Schlossberg, J., 1977, Cholesterol and cholesteryl ester content in normal and pathologic scale, J. Invest. Dermatol. 68: 206–209.PubMedCrossRefGoogle Scholar
  47. Shier, W. T., 1977, Inhibition of prostaglandin synthesis of lysolecithin, Biochem. Biophys. Res. Commun. 78: 1168–1174.CrossRefGoogle Scholar
  48. Shier, W. T., Baldwin, J. H., Nilsen-Hamilton, M., Hamilton, R. T., and Thanassi, N. M., 1976, Regulation of guanylate and adenylate cyclase activities by lysolecithin, Proc. Natl. Acad. Sci. USA 73: 1586–1590.PubMedCrossRefGoogle Scholar
  49. Skott, A., Mobacken, H., and Starmark, J. E., 1977, Exacerbation of psoriasis during lithium treatment, Br. J. Dermatol. 96: 445–448.PubMedCrossRefGoogle Scholar
  50. Sondergaard, J., Wadskov, S., Jensen, H. A. E., and Mikkelsen, H. I., 1976, Aggravation of psoriasis and occurrence of psoriasiform cutaneous eruptions in-duced by practolol (Eraldin°), Acta Derm, Venereol. 56: 239–243.Google Scholar
  51. Stankler, L., 1977, Histological findings in clinically normal palmer skin of patients with psoriasis, Br. J. Dermatol. 97: 131–134.PubMedCrossRefGoogle Scholar
  52. Stawiski, M. A., Powell, J. A., Lang, P. G., Schork, A., Duell, E. A., and Voorhees, J. J., 1975, Papaverine: Its effects on cyclic AMP in vitro and psoriasis in vivo, J. Invest. Dermatol. 64: 124–127.PubMedCrossRefGoogle Scholar
  53. Stawiski, M., Rusin, L., Schork, M. A., Burns, T., Duell, E., and Voorhees, J., 1976, Ro-20–1724 elevates epidermal cyclic AMP levels in vitro and improves psoriasis in vivo, Clin. Res. 24: 267.Google Scholar
  54. Sutherland, E. W., and Rail, T. W., 1960, The relation of adenosine-3’,5’-phosphate and phosphorylase to the actions of catecholamines and other hormones, Pharmacol. Rev. 12: 265–299.Google Scholar
  55. Truding, R., and Morel!, P., 1977, Effect of N6,02’-dibutyryl adenosine 3’:5’-monophosphate on the release of surface proteins by murine neuroblastoma cells, J. Biol. Chem. 252: 4850–4854.PubMedGoogle Scholar
  56. Turner, S. R., Tainer, J. A., and Lynn, W. S., 1975, Biogenesis of chemotactic molecules by the arachidonate lipoxygenase system of platelets, Nature (London) 257: 680–681.CrossRefGoogle Scholar
  57. Vassalli, J.-D., Hamilton, J., and Reich, E., 1976, Macrophage plasminogen activator: Modulation of enzyme production by anti-inflammatory steroids, mitotic inhibitors, and cyclic nucleotides, Cell 8: 271–281.PubMedCrossRefGoogle Scholar
  58. Voorhees, J. J., and Duell, E. A., 1971, Psoriasis as a possible defect of the adenyl cyclase-cyclic AMP cascade: A defective chalone mechanism? Arch. Dermatol. 104: 352–358.PubMedCrossRefGoogle Scholar
  59. Voorhees, J. J., Duell, E. A., Bass, L. J., Powell, J. A., and Harrell, E. R., 1972, Decreased cyclic AMP in the epidermis of lesions of psoriasis, Arch. Dermatol. 105: 695–701.Google Scholar
  60. Voorhees, J. J., Duell, E. A., Stawiski, M., and Harrell, E. R., 1974a, Cyclic nucleotide metabolism in normal and proliferating epidermis, in: Advances in Cyclic Nucleotide Research, Vol. 4 ( P. Greengard and G. A. Robison, eds.), pp. 117–162, Raven Press, New York.Google Scholar
  61. Voorhees, J. J., Colburn, N. H., Stawiski, M., Duell, E. A., Haddox, M., and Goldberg, N. D., 1974b, Imbalanced cyclic AMP and cyclic GMP levels in the rapidly dividing, incompletely differentiated epidermis of psoriasis, in: Control of Proliferation in Animal Cells ( B. Clarkson and R. Baserga, eds.), pp. 635–648, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.Google Scholar
  62. Voorhees, J. J., Marcelo, C. L., and Duell, E. A., 1975, Cyclic AMP, cyclic GMP, and glucocorticoids as potential metabolic regulators of epidermal proliferation and differentiation, J. Invest. Dermatol. 65: 179–190.PubMedCrossRefGoogle Scholar
  63. Voorhees, J. J., Duell, E. A., Anderson, T. F., Stawiski, M. A., Hammarström, S., and Hamberg, M., 1978, Pharmacological effects of glucocorticoid on arachidonic acid content of lesions of psoriasis, in: Advances in Prostaglandin and Thromboxane Research, Vol. 3 ( C. Galli, B. Samuelsson, and R. Paoletti, eds.), pp. 175–181, Raven Press, New York.Google Scholar
  64. Wallach, D., and Pastan, 1., 1976, Stimulation of guanylate cyclase of fibroblasts by free fatty acids, J. Biol. Chem. 251: 5802–5809.PubMedGoogle Scholar
  65. Wang, Y.-C., Pandey, G. N., Mendels, J., and Frazer, A., 1974, Effect of lithium on prostaglandin El-stimulated adenylate cyclase activity of human platelets, Biochem. Ph armacol. 23: 845–855.Google Scholar
  66. Wanger, L., and Sundqvist, K.-G., 1978, Membrane-associated actin in psoriatic epidermis, Acta Derm. Venereal. 58: 79–82.Google Scholar
  67. Watson, W., Cann, H. M., Farber, E. M., and Nall, M. L., 1972, The genetics of psoriasis, Arch. Dermatol. 105: 197–207.PubMedCrossRefGoogle Scholar
  68. Weinstein, G. D., and Frost, P., 1968, Abnormal cell pro- liferation in psoriasis, J. Invest. Dermatol. 50: 254–259.PubMedGoogle Scholar
  69. Whittenberger, B., and Glaser, L., 1977, Inhibition of DNA synthesis in cultures of 3T3 cells by isolated surface membranes, Proc. Natl. Acad. Sci. USA 74: 2251–2255.PubMedCrossRefGoogle Scholar
  70. Wiley, H., and Weinstein, G., 1977, Selective proliferative abnormality induced by propranolol in uninvolved psoriatic skin compared to normal skin, J. Invest. Dermatol. 68: 239.Google Scholar
  71. Yoshikawa, K., Adachi, K., Halprin, K. M., and Levine, V., 1975a, On the lack of response to catecholamine stimulation by the adenyl cyclase system in psoriatic lesions, Br. J. Dermatol. 92: 619–624.PubMedCrossRefGoogle Scholar
  72. Yoshikawa, K., Adachi, K., Halprin, K. M., and Levine, V., 1975b, Is the cyclic AMP in psoriatic epidermis low? Br. J. Dermatol. 93: 253–258.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1981

Authors and Affiliations

  • John J. Voorhees
    • 1
  1. 1.Department of DermatologyUniversity of Michigan Medical SchoolAnn ArborUSA

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