Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1998 Mar 15;330(Pt 3):1405–1409. doi: 10.1042/bj3301405

Metabolism of agmatine in macrophages: modulation by lipopolysaccharide and inhibitory cytokines.

M Sastre 1, E Galea 1, D Feinstein 1, D J Reis 1, S Regunathan 1
PMCID: PMC1219289  PMID: 9494113

Abstract

Agmatine is an amine derived from the decarboxylation of arginine by arginine decarboxylase (ADC) and metabolized to putrescine by agmatinase. While prevalent in bacteria and plants, agmatine and its metabolic enzymes have been recently identified in mammalian tissues. In the present study we sought to determine: (a) whether macrophages (cell line RAW 264.7) express ADC and agmatinase, and (b) if the enzymes are regulated by lipopolysaccharide (LPS), and/or by the inhibitory cytokines transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10) and interleukin-4 (IL-4). LPS induced a dose-dependent stimulation of agmatinase, while it decreased ADC, the effect in both cases being maximum at 20 h. As expected, LPS dose-dependently stimulated the inducible nitric oxide synthase activity (iNOS). A strong correlation was observed between the effects of LPS on the agmatine-related enzymes and iNOS. By contrast, exposure to IL-10 and TGF-beta caused a reduction in ADC and agmatinase, whereas IL-4 was ineffective on ADC, but reverted the LPS-induced increase of agmatinase. We conclude that the agmatine pathway may be an alternative metabolic route for arginine in macrophages, suggesting a regulatory role of agmatine during inflammation.

Full Text

The Full Text of this article is available as a PDF (267.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baydoun A. R., Bogle R. G., Pearson J. D., Mann G. E. Arginine uptake and metabolism in cultured murine macrophages. Agents Actions. 1993;38(Spec No):C127–C129. doi: 10.1007/BF01991160. [DOI] [PubMed] [Google Scholar]
  2. Bogdan C., Vodovotz Y., Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991 Dec 1;174(6):1549–1555. doi: 10.1084/jem.174.6.1549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bogdan C., Vodovotz Y., Paik J., Xie Q. W., Nathan C. Mechanism of suppression of nitric oxide synthase expression by interleukin-4 in primary mouse macrophages. J Leukoc Biol. 1994 Feb;55(2):227–233. doi: 10.1002/jlb.55.2.227. [DOI] [PubMed] [Google Scholar]
  4. Bogle R. G., Baydoun A. R., Pearson J. D., Moncada S., Mann G. E. L-arginine transport is increased in macrophages generating nitric oxide. Biochem J. 1992 May 15;284(Pt 1):15–18. doi: 10.1042/bj2840015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Boutard V., Havouis R., Fouqueray B., Philippe C., Moulinoux J. P., Baud L. Transforming growth factor-beta stimulates arginase activity in macrophages. Implications for the regulation of macrophage cytotoxicity. J Immunol. 1995 Aug 15;155(4):2077–2084. [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1016/0003-2697(76)90527-3. [DOI] [PubMed] [Google Scholar]
  7. Corraliza I. M., Soler G., Eichmann K., Modolell M. Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages. Biochem Biophys Res Commun. 1995 Jan 17;206(2):667–673. doi: 10.1006/bbrc.1995.1094. [DOI] [PubMed] [Google Scholar]
  8. Cunha F. Q., Moncada S., Liew F. Y. Interleukin-10 (IL-10) inhibits the induction of nitric oxide synthase by interferon-gamma in murine macrophages. Biochem Biophys Res Commun. 1992 Feb 14;182(3):1155–1159. doi: 10.1016/0006-291x(92)91852-h. [DOI] [PubMed] [Google Scholar]
  9. Daghigh F., Fukuto J. M., Ash D. E. Inhibition of rat liver arginase by an intermediate in NO biosynthesis, NG-hydroxy-L-arginine: implications for the regulation of nitric oxide biosynthesis by arginase. Biochem Biophys Res Commun. 1994 Jul 15;202(1):174–180. doi: 10.1006/bbrc.1994.1909. [DOI] [PubMed] [Google Scholar]
  10. Ding A., Nathan C. F., Graycar J., Derynck R., Stuehr D. J., Srimal S. Macrophage deactivating factor and transforming growth factors-beta 1 -beta 2 and -beta 3 inhibit induction of macrophage nitrogen oxide synthesis by IFN-gamma. J Immunol. 1990 Aug 1;145(3):940–944. [PubMed] [Google Scholar]
  11. Galea E., Regunathan S., Eliopoulos V., Feinstein D. L., Reis D. J. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochem J. 1996 May 15;316(Pt 1):247–249. doi: 10.1042/bj3160247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gazzinelli R. T., Oswald I. P., James S. L., Sher A. IL-10 inhibits parasite killing and nitrogen oxide production by IFN-gamma-activated macrophages. J Immunol. 1992 Mar 15;148(6):1792–1796. [PubMed] [Google Scholar]
  13. Granger D. L., Hibbs J. B., Jr, Perfect J. R., Durack D. T. Metabolic fate of L-arginine in relation to microbiostatic capability of murine macrophages. J Clin Invest. 1990 Jan;85(1):264–273. doi: 10.1172/JCI114422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hecker M., Nematollahi H., Hey C., Busse R., Racké K. Inhibition of arginase by NG-hydroxy-L-arginine in alveolar macrophages: implications for the utilization of L-arginine for nitric oxide synthesis. FEBS Lett. 1995 Feb 13;359(2-3):251–254. doi: 10.1016/0014-5793(95)00039-c. [DOI] [PubMed] [Google Scholar]
  15. Hrabák A., Antoni F., Csuka I. Differences in the arginase activity produced by resident and stimulated murine and rat peritoneal macrophages. Int J Biochem. 1991;23(10):997–1003. doi: 10.1016/0020-711x(91)90136-b. [DOI] [PubMed] [Google Scholar]
  16. Kalra S. P., Pearson E., Sahu A., Kalra P. S. Agmatine, a novel hypothalamic amine, stimulates pituitary luteinizing hormone release in vivo and hypothalamic luteinizing hormone-releasing hormone release in vitro. Neurosci Lett. 1995 Jul 21;194(3):165–168. doi: 10.1016/0304-3940(95)11750-q. [DOI] [PubMed] [Google Scholar]
  17. Li G., Regunathan S., Barrow C. J., Eshraghi J., Cooper R., Reis D. J. Agmatine: an endogenous clonidine-displacing substance in the brain. Science. 1994 Feb 18;263(5149):966–969. doi: 10.1126/science.7906055. [DOI] [PubMed] [Google Scholar]
  18. Lortie M. J., Novotny W. F., Peterson O. W., Vallon V., Malvey K., Mendonca M., Satriano J., Insel P., Thomson S. C., Blantz R. C. Agmatine, a bioactive metabolite of arginine. Production, degradation, and functional effects in the kidney of the rat. J Clin Invest. 1996 Jan 15;97(2):413–420. doi: 10.1172/JCI118430. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nussler A. K., Billiar T. R., Liu Z. Z., Morris S. M., Jr Coinduction of nitric oxide synthase and argininosuccinate synthetase in a murine macrophage cell line. Implications for regulation of nitric oxide production. J Biol Chem. 1994 Jan 14;269(2):1257–1261. [PubMed] [Google Scholar]
  20. Oswald I. P., Gazzinelli R. T., Sher A., James S. L. IL-10 synergizes with IL-4 and transforming growth factor-beta to inhibit macrophage cytotoxic activity. J Immunol. 1992 Jun 1;148(11):3578–3582. [PubMed] [Google Scholar]
  21. Raasch W., Regunathan S., Li G., Reis D. J. Agmatine, the bacterial amine, is widely distributed in mammalian tissues. Life Sci. 1995;56(26):2319–2330. doi: 10.1016/0024-3205(95)00226-v. [DOI] [PubMed] [Google Scholar]
  22. Regunathan S., Feinstein D. L., Raasch W., Reis D. J. Agmatine (decarboxylated arginine) is synthesized and stored in astrocytes. Neuroreport. 1995 Oct 2;6(14):1897–1900. doi: 10.1097/00001756-199510020-00018. [DOI] [PubMed] [Google Scholar]
  23. Regunathan S., Youngson C., Raasch W., Wang H., Reis D. J. Imidazoline receptors and agmatine in blood vessels: a novel system inhibiting vascular smooth muscle proliferation. J Pharmacol Exp Ther. 1996 Mar;276(3):1272–1282. [PubMed] [Google Scholar]
  24. Reis D. J., Regunathan S. Agmatine: a novel neurotransmitter? Adv Pharmacol. 1998;42:645–649. doi: 10.1016/s1054-3589(08)60834-0. [DOI] [PubMed] [Google Scholar]
  25. Sastre M., Regunathan S., Galea E., Reis D. J. Agmatinase activity in rat brain: a metabolic pathway for the degradation of agmatine. J Neurochem. 1996 Oct;67(4):1761–1765. doi: 10.1046/j.1471-4159.1996.67041761.x. [DOI] [PubMed] [Google Scholar]
  26. Sener A., Lebrun P., Blachier F., Malaisse W. J. Stimulus-secretion coupling of arginine-induced insulin release. Insulinotropic action of agmatine. Biochem Pharmacol. 1989 Jan 15;38(2):327–330. doi: 10.1016/0006-2952(89)90044-0. [DOI] [PubMed] [Google Scholar]
  27. Shearer J. D., Richards J. R., Mills C. D., Caldwell M. D. Differential regulation of macrophage arginine metabolism: a proposed role in wound healing. Am J Physiol. 1997 Feb;272(2 Pt 1):E181–E190. doi: 10.1152/ajpendo.1997.272.2.E181. [DOI] [PubMed] [Google Scholar]
  28. Smith F. F., Tres L. L., Kierszenbaum A. L. Ornithine decarboxylase activity during rat spermatogenesis in vivo and in vitro: selective effect of hormones and growth factors. J Cell Physiol. 1987 Nov;133(2):305–312. doi: 10.1002/jcp.1041330214. [DOI] [PubMed] [Google Scholar]
  29. Stuehr D. J., Nathan C. F. Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells. J Exp Med. 1989 May 1;169(5):1543–1555. doi: 10.1084/jem.169.5.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vodovotz Y., Bogdan C., Paik J., Xie Q. W., Nathan C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J Exp Med. 1993 Aug 1;178(2):605–613. doi: 10.1084/jem.178.2.605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. al-Ramadi B. K., Meissler J. J., Jr, Huang D., Eisenstein T. K. Immunosuppression induced by nitric oxide and its inhibition by interleukin-4. Eur J Immunol. 1992 Sep;22(9):2249–2254. doi: 10.1002/eji.1830220911. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES