Abstract
The purpose of this investigation was to elucidate the relationship of cyclic GMP and calcium to the immunologic discharge of lysosomal enzymes from purified human neutrophils. Contact of neutrophils with a variety of immunologic stimuli, including zymosan particles treated with either normal or rheumatoid arthritic (RA) serum, heat-aggregated (agg) IgG, particulate and immobilized agg IgG each treated with RA serum, and zymosan-treated serum, provoked the discharge of β-glucuronidase, but not cytoplasmic lactate dehydrogenase, and stimulated the accumulation of cyclic GMP. Both enzyme release and elevation of cyclic GMP levels required the presence of extracellular calcium as neither cellular event proceeded in its absence. Cholinergic enhancement of the immunologic secretion of β-glucuronidase from neutrophils by acetylcholine was associated with a concomitant accumulation of cyclic GMP. These actions of acetylcholine on neutrophils did not proceed in the absence of extracellular calcium. Whereas the concentrations of cyclic GMP in neutrophils were elevated by both immune reactants and a combination of the latter and acetylcholine, cyclic AMP levels remained unaltered. Thus, cyclic GMP, but not cyclic AMP, was associated with the immunologic and pharmacologic discharge of lysosomal enzymes from neutrophils. Contrariwise, cyclic AMP, but not cyclic GMP, was associated with inhibition of lysosomal enzyme release. For example, dibutyryl cyclic AMP and epinephrine inhibited the release of β-glucuronidase from neutrophils that was elicited by each of the immune reactants tested. Moreover, cyclic AMP levels in the cells were elevated markedly in every instance that enzyme discharge was inhibited by epinephrine. Epinephrine did not alter the neutrophil concentrations of cyclic GMP at times when those of cyclic AMP were elevated. The data in this report constitute partial evidence that the immunologic discharge of lysosomal enzymes from human neutrophils is mediated or signaled by intracellular cyclic GMP and that calcium is linked to this stimulation of enzyme secretion.
Full Text
The Full Text of this article is available as a PDF (772.9 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- George W. J., Polson J. B., O'Toole A. G., Goldberg N. D. Elevation of guanosine 3',5'-cyclic phosphate in rat heart after perfusion with acetylcholine. Proc Natl Acad Sci U S A. 1970 Jun;66(2):398–403. doi: 10.1073/pnas.66.2.398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- George W. J., Wilkerson R. D., Kadowitz P. J. Influence of acetylcholine on contractile force and cyclic nucleotide levels in the isolated perfused rat heart. J Pharmacol Exp Ther. 1973 Jan;184(1):228–235. [PubMed] [Google Scholar]
- Goldberg N. D., O'Dea R. F., Haddox M. K. Cyclic GMP. Adv Cyclic Nucleotide Res. 1973;3:155–223. [PubMed] [Google Scholar]
- Hardman J. G., Beavo J. A., Gray J. P., Chrisman T. D., Patterson W. D., Sutherland E. W. The formation and metabolism of cyclic GMP. Ann N Y Acad Sci. 1971 Dec 30;185:27–35. doi: 10.1111/j.1749-6632.1971.tb45232.x. [DOI] [PubMed] [Google Scholar]
- Hardman J. G., Robison G. A., Sutherland E. W. Cyclic nucleotides. Annu Rev Physiol. 1971;33:311–336. doi: 10.1146/annurev.ph.33.030171.001523. [DOI] [PubMed] [Google Scholar]
- Ignarro L. J., Colombo C. Enzyme release from polymorphonuclear leukocyte lysosomes: regulation by autonomic drugs and cyclic nucleotides. Science. 1973 Jun 15;180(4091):1181–1183. doi: 10.1126/science.180.4091.1181. [DOI] [PubMed] [Google Scholar]
- Ignarro L. J., Krassikoff N., Slywka J. Release of enzymes from a rat liver lysosome fraction: inhibition by catecholamines and cyclic3', 5'-adenosine monophosphate, stimulation by cholinergic agents and cyclic 3', 5'-guanosine monophosphate. J Pharmacol Exp Ther. 1973 Jul;186(1):86–99. [PubMed] [Google Scholar]
- Ignarro L. J., Lint T. F., George W. J. Hormonal control of lysosomal enzyme release from human neutrophils. Effects of autonomic agents on enzyme release, phagocytosis, and cylic nucleotide levels. J Exp Med. 1974 Jun 1;139(6):1395–1414. doi: 10.1084/jem.139.6.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ignarro L. J. Neutral protease release from human leukocytes regulated by neurohormones and cyclic nucleotides. Nat New Biol. 1973 Oct 3;245(144):151–154. doi: 10.1038/newbio245151a0. [DOI] [PubMed] [Google Scholar]
- Ignarro L. J. Nonphagocytic release of neutral protease and beta-glucuronidase from human neutrophils. Regulation by autonomic neurohormones and cyclic nucleotides. Arthritis Rheum. 1974 Jan-Feb;17(1):25–36. doi: 10.1002/art.1780170106. [DOI] [PubMed] [Google Scholar]
- Ignarro L. J., Paddock R. J., George W. J. Hormonal control of neutrophil lysosomal enzyme release: effect of epinephrine on adenosine 3',5'-monophosphate. Science. 1974 Mar 1;183(4127):855–857. doi: 10.1126/science.183.4127.855. [DOI] [PubMed] [Google Scholar]
- Ignarro L. J. Stimulation of phagocytic release of neutral protease from human neutrophils by cholinergic amines and cyclic 3',5'-guanosine monophosphate. J Immunol. 1974 Jan;112(1):210–214. [PubMed] [Google Scholar]
- Rubin R. P. The role of calcium in the release of neurotransmitter substances and hormones. Pharmacol Rev. 1970 Sep;22(3):389–428. [PubMed] [Google Scholar]
- WOODIN A. M., WIENEKE A. A. The accumulation of calcium by the polymorphonuclear leucocyte treated with staphylococcal leucocidin and its significance in the extrusion of protein. Biochem J. 1963 Jun;87:487–495. doi: 10.1042/bj0870487. [DOI] [PMC free article] [PubMed] [Google Scholar]