Home LiteratureArticle Details
PMID: 2851553 Published · ppublish English Journal Article

Function and stimulus-specific effects of phorbol 12-myristate 13-acetate on human polymorphonuclear neutrophils: autoregulatory role for protein kinase C in signal transduction.

Inflammation ·Vol. 12 ·No. 6 ·1988-12-00 ·Pages 597-611

Smith RJ, Justen JM, Sam LM

Abstract

Exposure of polymorphonuclear neutrophils (PMNs) to phorbol 12-myristate 13-acetate (PMA) resulted in a concentration-dependent (1-10 ng/ml) inhibition of granule exocytosis induced with the receptor-specific ligands, N-formyl-methionyl-leucyl-phenylalanine (FMLP), pepstatin A, 5(S),12(R)-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid (LTB4), and acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC). PMA exerted a marginal inhibitory effect on calcium ionophore A23187-induced PMN degranulation, and the PMA analog, 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), was inactive. However, PMA potentiated AGEPC, pepstatin A, FMLP, LTB4, and A23187-stimulated superoxide anion (O2-) production. The mobilization of intracellular sequestered calcium (Ca2+) by the receptor-specific ligands, as reflected by a rise in the cytosolic-free Ca2+ concentration ([Ca2+]i) in PMNs loaded with the Ca2+-sensitive dye, Fura-2, was suppressed by PMA. A protein kinase C (PKC) inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) reversed the PMA-mediated inhibition of PMN degranulation and intracellular CA2+ mobilization. However, another, but less potent PKC inhibitor, N-(2-guanidino-ethyl)-5-isoquinolinesulfonamide (HA1004), had no effect on the inhibition of PMN activation by PMA.

MeSH Terms
Exocytosis/drug effects Humans Leukotriene B4/pharmacology N-Formylmethionine Leucyl-Phenylalanine/pharmacology Neutrophils/drug effects,metabolism Pepstatins/pharmacology Platelet Activating Factor/pharmacology Protein Kinase C/metabolism Signal Transduction/drug effects Superoxides/metabolism Tetradecanoylphorbol Acetate/metabolism,pharmacology
Chemicals
Pepstatins Platelet Activating Factor Superoxides Streptomyces pepsin inhibitor Leukotriene B4 N-Formylmethionine Leucyl-Phenylalanine Protein Kinase C Tetradecanoylphorbol Acetate pepstatin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Smith R J
Department of Hypersensitivity Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Justen J M
Sam L M
References (53)
53 references, click to expand
  1. The effect of a protein kinase C inhibitor, H-7, on human neutrophil oxidative burst and degranulation.
    J Leukoc Biol. 1987 May;41(5):441-6 PMID: 3033114
  2. Intracellular control of human neutrophil secretion. I. C5a-induced stimulus-specific desensitization and the effects of cytochalasin B.
    J Immunol. 1978 Sep;121(3):851-5 PMID: 211165
  3. Inositol trisphosphate and diacylglycerol: two interacting second messengers.
    Annu Rev Biochem. 1987;56:159-93 PMID: 3304132
  4. Characterization of formylmethionyl-leucyl-phenylalanine stimulation of inositol trisphosphate accumulation in rabbit neutrophils.
    Mol Pharmacol. 1985 Jan;27(1):74-8 PMID: 2981403
  5. Phorbol myristate acetate and the calcium ionophore A23187 synergistically induce release of LTB4 by human neutrophils: involvement of protein kinase C activation in regulation of the 5-lipoxygenase pathway.
    J Immunol. 1987 May 15;138(10):3396-402 PMID: 3033073
  6. The inhibition of neutrophil responsiveness caused by phorbol esters is blocked by the protein kinase C inhibitor H7.
    Biochem Biophys Res Commun. 1986 May 29;137(1):50-60 PMID: 3013192
  7. The protein kinase C inhibitors H-7 and H-9 fail to inhibit human neutrophil activation.
    Biochem Biophys Res Commun. 1986 Mar 28;135(3):749-55 PMID: 3008744
  8. Role of a guanine nucleotide regulatory protein in the activation of phospholipase C by different chemoattractants.
    J Immunol. 1987 Jun 15;138(12):4374-80 PMID: 3108387
  9. ADP-ribosylation of the specific membrane protein by islet-activating protein, pertussis toxin, associated with inhibition of a chemotactic peptide-induced arachidonate release in neutrophils. A possible role of the toxin substrate in Ca2+-mobilizing biosignaling.
    J Biol Chem. 1984 Nov 25;259(22):13863-71 PMID: 6209272
  10. Characterization of effect of N-formyl-methionyl-leucyl-phenylalanine on leukotriene synthesis in human polymorphonuclear leukocytes.
    Inflammation. 1985 Jun;9(2):127-38 PMID: 2989173
  11. Effect of an inhibitor of protein kinase C on human polymorphonuclear leukocyte degranulation.
    Biochem Biophys Res Commun. 1987 Oct 29;148(2):747-54 PMID: 2825670
  12. Protein kinase C activation of physiological processes in human neutrophils at vanishingly small cytosolic Ca2+ levels.
    Nature. 1984 Aug 23-29;310(5979):691-3 PMID: 6236373
  13. Production of platelet-activating factor by stimulated human polymorphonuclear leukocytes. Correlation of synthesis with release, functional events, and leukotriene B4 metabolism.
    J Immunol. 1987 Jun 1;138(11):3918-26 PMID: 3035016
  14. Activation of NADPH oxidase of human neutrophils. Potentiation of chemotactic peptide by a diacylglycerol.
    Biochem Biophys Res Commun. 1984 Nov 30;125(1):367-73 PMID: 6095843
  15. Role of guanine nucleotide regulatory protein in polyphosphoinositide degradation and activation of phagocytic leukocytes by chemoattractants.
    J Cell Biochem. 1986;32(1):59-69 PMID: 3021789
  16. Stimulus amplification by PAF and LTB4 in human neutrophils.
    Pharmacol Res Commun. 1986 Aug;18 Suppl:51-9 PMID: 3022311
  17. Cytotaxin receptors of neutrophils: evidence that F-methionyl peptides and pepstatin share a common receptor.
    Infect Immun. 1979 Dec;26(3):996-9 PMID: 528062
  18. Phorbol myristate acetate mediates redistribution of protein kinase C in human neutrophils: potential role in the activation of the respiratory burst enzyme.
    J Immunol. 1985 Sep;135(3):2057-62 PMID: 3160785
  19. Chemoattractant-mediated stimulation of the respiratory burst in human polymorphonuclear leukocytes may require appearance of protein kinase activity in the cells' particulate fraction.
    Blood. 1986 Apr;67(4):909-13 PMID: 3006835
  20. Phorbol myristate acetate inhibits thrombin-stimulated Ca2+ mobilization and phosphatidylinositol 4,5-bisphosphate hydrolysis in human platelets.
    Proc Natl Acad Sci U S A. 1985 Jun;82(11):3859-62 PMID: 2987951
  21. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C.
    Biochemistry. 1984 Oct 9;23 (21):5036-41 PMID: 6238627
  22. Inositol trisphosphate, a novel second messenger in cellular signal transduction.
    Nature. 1984 Nov 22-28;312(5992):315-21 PMID: 6095092
  23. Modulation of human neutrophil superoxide anion generation by the calcium antagonist 8-(N,N-diethylamino)-octyl-(3,4,5-trimethoxy) benzoate hydrochloride.
    J Reticuloendothel Soc. 1981 Mar;29(3):215-25 PMID: 6260944
  24. Phorbol 12-myristate 13-acetate activates rabbit neutrophils without an apparent rise in the level of intracellular free calcium.
    Biochem Biophys Res Commun. 1983 Jul 29;114(2):638-45 PMID: 6411090
  25. Pepstatin A--a human leukocyte chemoattractant.
    Clin Immunol Immunopathol. 1979 Oct;14(2):244-50 PMID: 487669
  26. Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters.
    J Biol Chem. 1982 Jul 10;257(13):7847-51 PMID: 7085651
  27. Phorbol myristate acetate receptors in human polymorphonuclear neutrophils.
    J Immunol. 1985 Nov;135(5):3439-47 PMID: 4045196
  28. Protein kinase C-mediated negative-feedback inhibition of unstimulated and bombesin-stimulated polyphosphoinositide hydrolysis in Swiss-mouse 3T3 cells.
    Biochem J. 1987 Aug 1;245(3):631-9 PMID: 2822028
  29. Biochemical, metabolic and morphological characteristics of human neutrophil activation with pepstatin A.
    Immunology. 1983 Jun;49(2):367-77 PMID: 6303951
  30. Pepstatin, a new pepsin inhibitor produced by Actinomycetes.
    J Antibiot (Tokyo). 1970 May;23(5):259-62 PMID: 4912600
  31. Inhibitory action of phorbol myristate acetate on histamine secretion and polyphosphoinositide turnover induced by compound 48/80 in mast cells.
    Biochem Biophys Res Commun. 1985 Oct 15;132(1):110-7 PMID: 2415122
  32. Activation of NADPH oxidase in human neutrophils. Synergism between fMLP and the neutrophil products PAF and LTB4.
    Biochem Biophys Res Commun. 1985 Apr 16;128(1):297-304 PMID: 2985075
  33. Phorbol 12, myristate 13, acetate potentiates the respiratory burst while inhibits phosphoinositide hydrolysis and calcium mobilization by formyl-methionyl-leucyl-phenylalanine in human neutrophils.
    Biochem Biophys Res Commun. 1986 Mar 13;135(2):556-65 PMID: 3008726
  34. Inhibition of receptor-mediated release of arachidonic acid by pertussis toxin.
    Cell. 1984 Dec;39(2 Pt 1):301-8 PMID: 6094010
  35. Inhibition of chemotactic peptide-induced phosphoinositide hydrolysis by phorbol esters through the activation of protein kinase C in differentiated human leukemia (HL-60) cells.
    Cancer Res. 1986 Jul;46(7):3401-6 PMID: 3011248
  36. Synergism between A23187 and 1-oleoyl-2-acetyl-glycerol in superoxide production by human neutrophils.
    Biochem Biophys Res Commun. 1984 Nov 30;125(1):332-6 PMID: 6095841
  37. Modes of inhibitory action of protein kinase C in the chemotactic peptide-induced formation of inositol phosphates in differentiated human leukemic (HL-60) cells.
    J Biol Chem. 1987 May 15;262(14):6766-70 PMID: 3471761
  38. Arachidonate metabolites, platelet-activating factor, and the mobilization of protein kinase C in human polymorphonuclear neutrophils.
    J Immunol. 1987 Mar 15;138(6):1889-95 PMID: 3029224
  39. A new generation of Ca2+ indicators with greatly improved fluorescence properties.
    J Biol Chem. 1985 Mar 25;260(6):3440-50 PMID: 3838314
  40. Model for leukocyte regulation by chemoattractant receptors: roles of a guanine nucleotide regulatory protein and polyphosphoinositide metabolism.
    J Leukoc Biol. 1986 Dec;40(6):785-800 PMID: 3023515
  41. Nucleotide regulatory protein-mediated activation of phospholipase C in human polymorphonuclear leukocytes is disrupted by phorbol esters.
    J Biol Chem. 1987 May 5;262(13):6121-7 PMID: 3032956
  42. Competitive inhibition by diacylglycerol of specific phorbol ester binding.
    Proc Natl Acad Sci U S A. 1984 Jan;81(2):607-10 PMID: 6320198
  43. Effect of phorbol 12-myristate 13-acetate and its analogue 4 alpha-phorbol 12,13-didecanoate on protein phosphorylation and lysosomal enzyme release in rabbit neutrophils.
    J Biol Chem. 1984 Jul 10;259(13):8605-11 PMID: 6429145
  44. The role of protein kinase C in cell surface signal transduction and tumour promotion.
    Nature. 1984 Apr 19-25;308(5961):693-8 PMID: 6232463
  45. Pepstatin A-induced degranulation and superoxide anion generation by human neutrophils.
    Clin Immunol Immunopathol. 1982 Jan;22(1):83-93 PMID: 6288295
  46. Role of protein kinases in stimulation of human polymorphonuclear leukocyte oxidative metabolism by various agonists. Differential effects of a novel protein kinase inhibitor.
    J Clin Invest. 1986 Jan;77(1):61-5 PMID: 3003155
  47. 1,2-Diacylglycerol and phorbol ester inhibit agonist-induced formation of inositol phosphates in human platelets: possible implications for negative feedback regulation of inositol phospholipid hydrolysis.
    Proc Natl Acad Sci U S A. 1985 May;82(9):2623-6 PMID: 2986126
  48. Protein kinase C phosphorylates the inhibitory guanine-nucleotide-binding regulatory component and apparently suppresses its function in hormonal inhibition of adenylate cyclase.
    Eur J Biochem. 1985 Sep 2;151(2):431-7 PMID: 3161729
  49. Stimulus response coupling in the human neutrophil. II. Temporal analysis of changes in cytosolic calcium and calcium efflux.
    J Biol Chem. 1984 Apr 10;259(7):4076-82 PMID: 6323455
  50. 1-(5-Isoquinolinesulfonyl)-2-methylpiperazine (H-7) is a selective inhibitor of protein kinase C in rabbit platelets.
    Biochem Biophys Res Commun. 1984 Nov 30;125(1):258-64 PMID: 6239622
  51. Phorbol esters inhibit the fMet-Leu-Phe- and leukotriene B4-stimulated calcium mobilization and enzyme secretion in rabbit neutrophils.
    J Biol Chem. 1985 Feb 25;260(4):2125-31 PMID: 2982810
  52. Phorbol 12-myristate, 13-acetate potentiates the action of the calcium ionophore in stimulating arachidonic acid release and production of phosphatidic acid in rabbit neutrophils.
    Biochem Biophys Res Commun. 1985 Apr 30;128(2):594-600 PMID: 2986620
  53. Inhibition of human neutrophil chemotaxis by the protein kinase inhibitor, 1-(5-isoquinolinesulfonyl) piperazine.
    J Immunol. 1987 Nov 1;139(9):3055-61 PMID: 2822802
Article Info
Journal
Inflammation
Abbr.
Inflammation
ISSN
0360-3997
DOI
10.1007/BF00914321
Published
1988-12-00
Pages
597-611
Language
English
Region
United States
NLM ID
7600105
Subset
IM
External Links
PubMed source DOI: 10.1007/BF00914321 View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2