Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2001 Apr 1;355(Pt 1):29–38. doi: 10.1042/0264-6021:3550029

Alpha-melanocyte-related tripeptide, Lys-d-Pro-Val, ameliorates endotoxin-induced nuclear factor kappaB translocation and activation: evidence for involvement of an interleukin-1beta193-195 receptor antagonism in the alveolar epithelium.

J J Haddad 1, R Lauterbach 1, N E Saadé 1, B Safieh-Garabedian 1, S C Land 1
PMCID: PMC1221708  PMID: 11256945

Abstract

The potential anti-inflammatory role of alpha-melanocyte-stimulating hormone (alpha-MSH)-related tripeptide, lysine(11)-D-proline-valine(13) (KDPV), an analogue of interleukin (IL)-1beta(193-195) and an antagonist of IL-1beta/prostaglandin E(2), is not well characterized in the alveolar epithelium. In a model of foetal alveolar type II epithelial cells in vitro, we showed that lipopolysaccharide endotoxin (LPS) differentially, but selectively, induced the nuclear subunit composition of nuclear factor kappaB(1) (NF-kappaB(1)) (p50), RelA (p65) and c-Rel (p75), in parallel to up-regulating the DNA-binding activity (supershift indicating the presence of the p50-p65 complex). LPS accelerated the degradation of inhibitory kappaB-alpha (IkappaB-alpha), accompanied by enhancing its phosphorylation in the cytosolic compartment but not in the nucleus. KDPV suppressed, in a dose-dependent manner, the nuclear localization of p50, p65 and p75, an effect that led to the subsequent inhibition of NF-kappaB activation. Interleukin-1 receptor antagonist (IL-1ra) decreased the nuclear abundance of p50, p65 and p75, and subsequently depressed the DNA-binding activity induced by LPS. Analysis of the mechanism involved in the KDPV- and IL-1ra-mediated inhibition of NF-kappaB nuclear localization revealed a reversal in IkappaB-alpha phosphorylation and degradation, followed by cytosolic accumulation. LPS induced endogenous IL-1beta biosynthesis in a time-dependent manner; the administration of exogenous recombinant human interleukin 1 (rhIL-1) resulted in a dose-dependent activation of NF-kappaB. KDPV and IL-1ra abrogated the effect of rhIL-1. Pretreatment with the non-steroidal anti-inflammatory drug (NSAID) indomethacin, an inhibitor of cyclo-oxygenase, blocked the LPS-induced activation of NF-kappaB. These results indicate the involvement of prostanoid-dependent (NSAID-sensitive) and IL-1-dependent (IL-1ra-sensitive) mechanisms mediating LPS-induced NF-kappaB translocation and activation, a pathway that is regulated, in part, by a negative feedback mechanism transduced through IkappaB-alpha, the major cytosolic inhibitor of NF-kappaB.

Full Text

The Full Text of this article is available as a PDF (420.2 KB).

Selected References

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

  1. Bhardwaj R. S., Schwarz A., Becher E., Mahnke K., Aragane Y., Schwarz T., Luger T. A. Pro-opiomelanocortin-derived peptides induce IL-10 production in human monocytes. J Immunol. 1996 Apr 1;156(7):2517–2521. [PubMed] [Google Scholar]
  2. Catania A., Lipton J. M. alpha-Melanocyte stimulating hormone in the modulation of host reactions. Endocr Rev. 1993 Oct;14(5):564–576. doi: 10.1210/edrv-14-5-564. [DOI] [PubMed] [Google Scholar]
  3. Chiao H., Foster S., Thomas R., Lipton J., Star R. A. Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation. J Clin Invest. 1996 May 1;97(9):2038–2044. doi: 10.1172/JCI118639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chiao H., Kohda Y., McLeroy P., Craig L., Housini I., Star R. A. Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest. 1997 Mar 15;99(6):1165–1172. doi: 10.1172/JCI119272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. DiDonato J. A., Hayakawa M., Rothwarf D. M., Zandi E., Karin M. A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature. 1997 Aug 7;388(6642):548–554. doi: 10.1038/41493. [DOI] [PubMed] [Google Scholar]
  6. Dinarello C. A. Interleukin-1. Rev Infect Dis. 1984 Jan-Feb;6(1):51–95. doi: 10.1093/clinids/6.1.51. [DOI] [PubMed] [Google Scholar]
  7. Ferreira S. H., Lorenzetti B. B., Bristow A. F., Poole S. Interleukin-1 beta as a potent hyperalgesic agent antagonized by a tripeptide analogue. Nature. 1988 Aug 25;334(6184):698–700. doi: 10.1038/334698a0. [DOI] [PubMed] [Google Scholar]
  8. Fu K., Sarras M. P., Jr, De Lisle R. C., Andrews G. K. Expression of oxidative stress-responsive genes and cytokine genes during caerulein-induced acute pancreatitis. Am J Physiol. 1997 Sep;273(3 Pt 1):G696–G705. doi: 10.1152/ajpgi.1997.273.3.G696. [DOI] [PubMed] [Google Scholar]
  9. Galimberti D., Baron P., Meda L., Prat E., Scarpini E., Delgado R., Catania A., Lipton J. M., Scarlato G. Alpha-MSH peptides inhibit production of nitric oxide and tumor necrosis factor-alpha by microglial cells activated with beta-amyloid and interferon gamma. Biochem Biophys Res Commun. 1999 Sep 16;263(1):251–256. doi: 10.1006/bbrc.1999.1276. [DOI] [PubMed] [Google Scholar]
  10. Ghosh S., Baltimore D. Activation in vitro of NF-kappa B by phosphorylation of its inhibitor I kappa B. Nature. 1990 Apr 12;344(6267):678–682. doi: 10.1038/344678a0. [DOI] [PubMed] [Google Scholar]
  11. Haddad J. J., Land S. C. O(2)-evoked regulation of HIF-1alpha and NF-kappaB in perinatal lung epithelium requires glutathione biosynthesis. Am J Physiol Lung Cell Mol Physiol. 2000 Mar;278(3):L492–L503. doi: 10.1152/ajplung.2000.278.3.L492. [DOI] [PubMed] [Google Scholar]
  12. Haddad J. J., Land S. C. The differential expression of apoptosis factors in the alveolar epithelium is redox sensitive and requires NF-kappaB (RelA)-selective targeting. Biochem Biophys Res Commun. 2000 Apr 29;271(1):257–267. doi: 10.1006/bbrc.2000.2607. [DOI] [PubMed] [Google Scholar]
  13. Haddad J. J., Olver R. E., Land S. C. Antioxidant/pro-oxidant equilibrium regulates HIF-1alpha and NF-kappa B redox sensitivity. Evidence for inhibition by glutathione oxidation in alveolar epithelial cells. J Biol Chem. 2000 Jul 14;275(28):21130–21139. doi: 10.1074/jbc.M000737200. [DOI] [PubMed] [Google Scholar]
  14. Haycock J. W., Wagner M., Morandini R., Ghanem G., Rennie I. G., Mac Neil S. Alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation in human melanocytes and melanoma cells. J Invest Dermatol. 1999 Oct;113(4):560–566. doi: 10.1046/j.1523-1747.1999.00739.x. [DOI] [PubMed] [Google Scholar]
  15. Hiltz M. E., Lipton J. M. Alpha-MSH peptides inhibit acute inflammation and contact sensitivity. Peptides. 1990 Sep-Oct;11(5):979–982. doi: 10.1016/0196-9781(90)90020-6. [DOI] [PubMed] [Google Scholar]
  16. Huang Q. H., Hruby V. J., Tatro J. B. Systemic alpha-MSH suppresses LPS fever via central melanocortin receptors independently of its suppression of corticosterone and IL-6 release. Am J Physiol. 1998 Aug;275(2 Pt 2):R524–R530. doi: 10.1152/ajpregu.1998.275.2.R524. [DOI] [PubMed] [Google Scholar]
  17. Ichiyama T., Sakai T., Catania A., Barsh G. S., Furukawa S., Lipton J. M. Inhibition of peripheral NF-kappaB activation by central action of alpha-melanocyte-stimulating hormone. J Neuroimmunol. 1999 Oct 29;99(2):211–217. doi: 10.1016/s0165-5728(99)00122-8. [DOI] [PubMed] [Google Scholar]
  18. Ichiyama T., Sakai T., Catania A., Barsh G. S., Furukawa S., Lipton J. M. Systemically administered alpha-melanocyte-stimulating peptides inhibit NF-kappaB activation in experimental brain inflammation. Brain Res. 1999 Jul 31;836(1-2):31–37. doi: 10.1016/s0006-8993(99)01584-x. [DOI] [PubMed] [Google Scholar]
  19. Ichiyama T., Zhao H., Catania A., Furukawa S., Lipton J. M. alpha-melanocyte-stimulating hormone inhibits NF-kappaB activation and IkappaBalpha degradation in human glioma cells and in experimental brain inflammation. Exp Neurol. 1999 Jun;157(2):359–365. doi: 10.1006/exnr.1999.7064. [DOI] [PubMed] [Google Scholar]
  20. Manna S. K., Aggarwal B. B. Alpha-melanocyte-stimulating hormone inhibits the nuclear transcription factor NF-kappa B activation induced by various inflammatory agents. J Immunol. 1998 Sep 15;161(6):2873–2880. [PubMed] [Google Scholar]
  21. Mitchell J. A., Akarasereenont P., Thiemermann C., Flower R. J., Vane J. R. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11693–11697. doi: 10.1073/pnas.90.24.11693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Poole S., Bristow A. F., Lorenzetti B. B., Das R. E., Smith T. W., Ferreira S. H. Peripheral analgesic activities of peptides related to alpha-melanocyte stimulating hormone and interleukin-1 beta 193-195. Br J Pharmacol. 1992 Jun;106(2):489–492. doi: 10.1111/j.1476-5381.1992.tb14361.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Richards D. B., Lipton J. M. Effect of alpha-MSH 11-13 (lysine-proline-valine) on fever in the rabbit. Peptides. 1984 Jul-Aug;5(4):815–817. doi: 10.1016/0196-9781(84)90027-5. [DOI] [PubMed] [Google Scholar]
  24. Safieh-Garabedian B., Kanaan S. A., Haddad J. J., Jaoude P. A., Jabbur S. J., Saadé N. E. Involvement of interleukin-1 beta, nerve growth factor and prostaglandin E2 in endotoxin-induced localized inflammatory hyperalgesia. Br J Pharmacol. 1997 Aug;121(8):1619–1626. doi: 10.1038/sj.bjp.0701313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Saugstad O. D. Oxygen radicals and pulmonary damage. Pediatr Pulmonol. 1985 May-Jun;1(3):167–175. doi: 10.1002/ppul.1950010308. [DOI] [PubMed] [Google Scholar]
  26. Schreck R., Meier B., Männel D. N., Dröge W., Baeuerle P. A. Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med. 1992 May 1;175(5):1181–1194. doi: 10.1084/jem.175.5.1181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sen R., Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986 Aug 29;46(5):705–716. doi: 10.1016/0092-8674(86)90346-6. [DOI] [PubMed] [Google Scholar]
  28. Siebenlist U., Franzoso G., Brown K. Structure, regulation and function of NF-kappa B. Annu Rev Cell Biol. 1994;10:405–455. doi: 10.1146/annurev.cb.10.110194.002201. [DOI] [PubMed] [Google Scholar]
  29. Star R. A., Rajora N., Huang J., Stock R. C., Catania A., Lipton J. M. Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8016–8020. doi: 10.1073/pnas.92.17.8016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Taherzadeh S., Sharma S., Chhajlani V., Gantz I., Rajora N., Demitri M. T., Kelly L., Zhao H., Ichiyama T., Catania A. alpha-MSH and its receptors in regulation of tumor necrosis factor-alpha production by human monocyte/macrophages. Am J Physiol. 1999 May;276(5 Pt 2):R1289–R1294. doi: 10.1152/ajpregu.1999.276.5.R1289. [DOI] [PubMed] [Google Scholar]
  31. Tsatmali M., Graham A., Szatkowski D., Ancans J., Manning P., McNeil C. J., Graham A. M., Thody A. J. alpha-melanocyte-stimulating hormone modulates nitric oxide production in melanocytes. J Invest Dermatol. 2000 Mar;114(3):520–526. doi: 10.1046/j.1523-1747.2000.00879.x. [DOI] [PubMed] [Google Scholar]
  32. Weiss J. M., Sundar S. K., Cierpial M. A., Ritchie J. C. Effects of interleukin-1 infused into brain are antagonized by alpha-MSH in a dose-dependent manner. Eur J Pharmacol. 1991 Jan 3;192(1):177–179. doi: 10.1016/0014-2999(91)90087-7. [DOI] [PubMed] [Google Scholar]
  33. Woronicz J. D., Gao X., Cao Z., Rothe M., Goeddel D. V. IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. Science. 1997 Oct 31;278(5339):866–869. doi: 10.1126/science.278.5339.866. [DOI] [PubMed] [Google Scholar]

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

RESOURCES