Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Nov 7;92(23):10738–10741. doi: 10.1073/pnas.92.23.10738

Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells.

B D Gitter 1, L M Cox 1, R E Rydel 1, P C May 1
PMCID: PMC40687  PMID: 7479875

Abstract

Neurodegenerative processes in Alzheimer disease (AD) are thought to be driven in part by the deposition of amyloid beta (A beta), a 39- to 43-amino acid peptide product resulting from an alternative cleavage of amyloid precursor protein. Recent descriptions of in vitro neurotoxic effects of A beta support this hypothesis and suggest toxicity might be mediated by A beta-induced neuronal calcium disregulation. In addition, it has been reported that "aging" A beta results in increased toxic potency due to peptide aggregation and formation of a beta-sheet secondary structure. In addition, A beta might also promote neuropathology indirectly by activating immune/inflammatory pathways in affected areas of the brain (e.g., cortex and hippocampus). Here we report that A beta can modulate cytokine secretion [interleukins 6 and 8 (IL-6 and IL-8)] from human astrocytoma cells (U-373 MG). Freshly prepared and aged A beta modestly stimulated IL-6 and IL-8 secretion from U-373 MG cells. However, in the presence of interleukin-1 beta (IL-1 beta), aged, but not fresh, A beta markedly potentiated (3- to 8-fold) cytokine release. In contrast, aged A beta did not potentiate substance P (NK-1)- or histamine (H1)-stimulated cytokine production. Further studies showed that IL-1 beta-induced cytokine release was potentiated by A beta-(25-35), while A beta-(1-16) was inactive. Calcium disregulation may be responsible for the effects of A beta on cytokine production, since the calcium ionophore A23187 similarly potentiated IL-1 beta-induced cytokine secretion and EGTA treatment blocked either A beta or A23187 activity. Thus, chronic neurodegeneration in AD-affected brain regions may be mediated in part by the ability of A beta to exacerbate inflammatory pathways in a conformation-dependent manner.

Full text

PDF
10738

Images in this article

10739Fig. 1
on p.10739

Selected References

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

  1. Aisen P. S., Davis K. L. Inflammatory mechanisms in Alzheimer's disease: implications for therapy. Am J Psychiatry. 1994 Aug;151(8):1105–1113. doi: 10.1176/ajp.151.8.1105. [DOI] [PubMed] [Google Scholar]
  2. Aloisi F., Carè A., Borsellino G., Gallo P., Rosa S., Bassani A., Cabibbo A., Testa U., Levi G., Peschle C. Production of hemolymphopoietic cytokines (IL-6, IL-8, colony-stimulating factors) by normal human astrocytes in response to IL-1 beta and tumor necrosis factor-alpha. J Immunol. 1992 Oct 1;149(7):2358–2366. [PubMed] [Google Scholar]
  3. Araujo D. M., Cotman C. W. Beta-amyloid stimulates glial cells in vitro to produce growth factors that accumulate in senile plaques in Alzheimer's disease. Brain Res. 1992 Jan 8;569(1):141–145. doi: 10.1016/0006-8993(92)90380-r. [DOI] [PubMed] [Google Scholar]
  4. Barnum S. R., Jones J. L., Benveniste E. N. Interleukin-1 and tumor necrosis factor-mediated regulation of C3 gene expression in human astroglioma cells. Glia. 1993 Mar;7(3):225–236. doi: 10.1002/glia.440070306. [DOI] [PubMed] [Google Scholar]
  5. Bauer J., Strauss S., Schreiter-Gasser U., Ganter U., Schlegel P., Witt I., Yolk B., Berger M. Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer's disease cortices. FEBS Lett. 1991 Jul 8;285(1):111–114. doi: 10.1016/0014-5793(91)80737-n. [DOI] [PubMed] [Google Scholar]
  6. Bellinger F. P., Madamba S., Siggins G. R. Interleukin 1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus. Brain Res. 1993 Nov 19;628(1-2):227–234. doi: 10.1016/0006-8993(93)90959-q. [DOI] [PubMed] [Google Scholar]
  7. Breitner J. C., Gau B. A., Welsh K. A., Plassman B. L., McDonald W. M., Helms M. J., Anthony J. C. Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin control study. Neurology. 1994 Feb;44(2):227–232. doi: 10.1212/wnl.44.2.227. [DOI] [PubMed] [Google Scholar]
  8. Buxbaum J. D., Oishi M., Chen H. I., Pinkas-Kramarski R., Jaffe E. A., Gandy S. E., Greengard P. Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor. Proc Natl Acad Sci U S A. 1992 Nov 1;89(21):10075–10078. doi: 10.1073/pnas.89.21.10075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cadman E. D., Witte D. G., Lee C. M. Regulation of the release of interleukin-6 from human astrocytoma cells. J Neurochem. 1994 Sep;63(3):980–987. doi: 10.1046/j.1471-4159.1994.63030980.x. [DOI] [PubMed] [Google Scholar]
  10. Frederickson R. C. Astroglia in Alzheimer's disease. Neurobiol Aging. 1992 Mar-Apr;13(2):239–253. doi: 10.1016/0197-4580(92)90036-w. [DOI] [PubMed] [Google Scholar]
  11. Giaccone G., Tagliavini F., Linoli G., Bouras C., Frigerio L., Frangione B., Bugiani O. Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques. Neurosci Lett. 1989 Feb 13;97(1-2):232–238. doi: 10.1016/0304-3940(89)90169-9. [DOI] [PubMed] [Google Scholar]
  12. Gitter B. D., Regoli D., Howbert J. J., Glasebrook A. L., Waters D. C. Interleukin-6 secretion from human astrocytoma cells induced by substance P. J Neuroimmunol. 1994 Apr;51(1):101–108. doi: 10.1016/0165-5728(94)90134-1. [DOI] [PubMed] [Google Scholar]
  13. Giulian D., Lachman L. B. Interleukin-1 stimulation of astroglial proliferation after brain injury. Science. 1985 Apr 26;228(4698):497–499. doi: 10.1126/science.3872478. [DOI] [PubMed] [Google Scholar]
  14. Glenner G. G., Wong C. W. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984 May 16;120(3):885–890. doi: 10.1016/s0006-291x(84)80190-4. [DOI] [PubMed] [Google Scholar]
  15. Goldgaber D., Harris H. W., Hla T., Maciag T., Donnelly R. J., Jacobsen J. S., Vitek M. P., Gajdusek D. C. Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7606–7610. doi: 10.1073/pnas.86.19.7606. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Griffin W. S., Sheng J. G., Roberts G. W., Mrak R. E. Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution. J Neuropathol Exp Neurol. 1995 Mar;54(2):276–281. doi: 10.1097/00005072-199503000-00014. [DOI] [PubMed] [Google Scholar]
  17. Griffin W. S., Stanley L. C., Ling C., White L., MacLeod V., Perrot L. J., White C. L., 3rd, Araoz C. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7611–7615. doi: 10.1073/pnas.86.19.7611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Haga S., Ikeda K., Sato M., Ishii T. Synthetic Alzheimer amyloid beta/A4 peptides enhance production of complement C3 component by cultured microglial cells. Brain Res. 1993 Jan 22;601(1-2):88–94. doi: 10.1016/0006-8993(93)91698-r. [DOI] [PubMed] [Google Scholar]
  19. Hardy J., Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci. 1991 Oct;12(10):383–388. doi: 10.1016/0165-6147(91)90609-v. [DOI] [PubMed] [Google Scholar]
  20. Kasahara T., Mukaida N., Yamashita K., Yagisawa H., Akahoshi T., Matsushima K. IL-1 and TNF-alpha induction of IL-8 and monocyte chemotactic and activating factor (MCAF) mRNA expression in a human astrocytoma cell line. Immunology. 1991 Sep;74(1):60–67. [PMC free article] [PubMed] [Google Scholar]
  21. Kasahara T., Yagisawa H., Yamashita K., Yamaguchi Y., Akiyama Y. IL1 induces proliferation and IL6 mRNA expression in a human astrocytoma cell line: positive and negative modulation by chorela toxin and cAMP. Biochem Biophys Res Commun. 1990 Mar 30;167(3):1242–1248. doi: 10.1016/0006-291x(90)90657-9. [DOI] [PubMed] [Google Scholar]
  22. Lee S. C., Liu W., Dickson D. W., Brosnan C. F., Berman J. W. Cytokine production by human fetal microglia and astrocytes. Differential induction by lipopolysaccharide and IL-1 beta. J Immunol. 1993 Apr 1;150(7):2659–2667. [PubMed] [Google Scholar]
  23. Li W. Y., Czilli D. L., Simmons L. K. Neuronal membrane conductance activated by amyloid beta peptide: importance of peptide conformation. Brain Res. 1995 Jun 5;682(1-2):207–211. doi: 10.1016/0006-8993(95)00264-q. [DOI] [PubMed] [Google Scholar]
  24. Lorenzo A., Yankner B. A. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12243–12247. doi: 10.1073/pnas.91.25.12243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Mann D. M. Cerebral amyloidosis, ageing and Alzheimer's disease; a contribution from studies on Down's syndrome. Neurobiol Aging. 1989 Sep-Oct;10(5):397–414. doi: 10.1016/0197-4580(89)90073-0. [DOI] [PubMed] [Google Scholar]
  26. Mattson M. P., Barger S. W., Cheng B., Lieberburg I., Smith-Swintosky V. L., Rydel R. E. beta-Amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer's disease. Trends Neurosci. 1993 Oct;16(10):409–414. doi: 10.1016/0166-2236(93)90009-b. [DOI] [PubMed] [Google Scholar]
  27. Mattson M. P., Cheng B., Davis D., Bryant K., Lieberburg I., Rydel R. E. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci. 1992 Feb;12(2):376–389. doi: 10.1523/JNEUROSCI.12-02-00376.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Mattson M. P., Tomaselli K. J., Rydel R. E. Calcium-destabilizing and neurodegenerative effects of aggregated beta-amyloid peptide are attenuated by basic FGF. Brain Res. 1993 Sep 3;621(1):35–49. doi: 10.1016/0006-8993(93)90295-x. [DOI] [PubMed] [Google Scholar]
  29. May P. C., Boggs L. N., Fuson K. S. Neurotoxicity of human amylin in rat primary hippocampal cultures: similarity to Alzheimer's disease amyloid-beta neurotoxicity. J Neurochem. 1993 Dec;61(6):2330–2333. doi: 10.1111/j.1471-4159.1993.tb07480.x. [DOI] [PubMed] [Google Scholar]
  30. May P. C., Gitter B. D., Waters D. C., Simmons L. K., Becker G. W., Small J. S., Robison P. M. beta-Amyloid peptide in vitro toxicity: lot-to-lot variability. Neurobiol Aging. 1992 Sep-Oct;13(5):605–607. doi: 10.1016/0197-4580(92)90064-5. [DOI] [PubMed] [Google Scholar]
  31. McGeer P. L., McGeer E., Rogers J., Sibley J. Anti-inflammatory drugs and Alzheimer disease. Lancet. 1990 Apr 28;335(8696):1037–1037. doi: 10.1016/0140-6736(90)91101-f. [DOI] [PubMed] [Google Scholar]
  32. McGeer P. L., Rogers J., McGeer E. G. Neuroimmune mechanisms in Alzheimer disease pathogenesis. Alzheimer Dis Assoc Disord. 1994 Fall;8(3):149–158. doi: 10.1097/00002093-199408030-00001. [DOI] [PubMed] [Google Scholar]
  33. Moynagh P. N., Williams D. C., O'Neill L. A. Activation of NF-kappa B and induction of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 expression in human glial cells by IL-1. Modulation by antioxidants. J Immunol. 1994 Sep 15;153(6):2681–2690. [PubMed] [Google Scholar]
  34. Nishida T., Nakai S., Kawakami T., Aihara K., Nishino N., Hirai Y. Dexamethasone regulation of the expression of cytokine mRNAs induced by interleukin-1 in the astrocytoma cell line U373MG. FEBS Lett. 1989 Jan 16;243(1):25–29. doi: 10.1016/0014-5793(89)81210-4. [DOI] [PubMed] [Google Scholar]
  35. Pike C. J., Burdick D., Walencewicz A. J., Glabe C. G., Cotman C. W. Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J Neurosci. 1993 Apr;13(4):1676–1687. doi: 10.1523/JNEUROSCI.13-04-01676.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pike C. J., Walencewicz-Wasserman A. J., Kosmoski J., Cribbs D. H., Glabe C. G., Cotman C. W. Structure-activity analyses of beta-amyloid peptides: contributions of the beta 25-35 region to aggregation and neurotoxicity. J Neurochem. 1995 Jan;64(1):253–265. doi: 10.1046/j.1471-4159.1995.64010253.x. [DOI] [PubMed] [Google Scholar]
  37. Pike C. J., Walencewicz A. J., Glabe C. G., Cotman C. W. In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 1991 Nov 1;563(1-2):311–314. doi: 10.1016/0006-8993(91)91553-d. [DOI] [PubMed] [Google Scholar]
  38. Pontén J., Macintyre E. H. Long term culture of normal and neoplastic human glia. Acta Pathol Microbiol Scand. 1968;74(4):465–486. doi: 10.1111/j.1699-0463.1968.tb03502.x. [DOI] [PubMed] [Google Scholar]
  39. Potter H. The involvement of astrocytes and an acute phase response in the amyloid deposition of Alzheimer's disease. Prog Brain Res. 1992;94:447–458. doi: 10.1016/s0079-6123(08)61772-0. [DOI] [PubMed] [Google Scholar]
  40. Rogers J., Kirby L. C., Hempelman S. R., Berry D. L., McGeer P. L., Kaszniak A. W., Zalinski J., Cofield M., Mansukhani L., Willson P. Clinical trial of indomethacin in Alzheimer's disease. Neurology. 1993 Aug;43(8):1609–1611. doi: 10.1212/wnl.43.8.1609. [DOI] [PubMed] [Google Scholar]
  41. Rothwell N. J. Functions and mechanisms of interleukin 1 in the brain. Trends Pharmacol Sci. 1991 Nov;12(11):430–436. doi: 10.1016/0165-6147(91)90623-z. [DOI] [PubMed] [Google Scholar]
  42. Selkoe D. J. Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease. Annu Rev Cell Biol. 1994;10:373–403. doi: 10.1146/annurev.cb.10.110194.002105. [DOI] [PubMed] [Google Scholar]
  43. Simmons L. K., May P. C., Tomaselli K. J., Rydel R. E., Fuson K. S., Brigham E. F., Wright S., Lieberburg I., Becker G. W., Brems D. N. Secondary structure of amyloid beta peptide correlates with neurotoxic activity in vitro. Mol Pharmacol. 1994 Mar;45(3):373–379. [PubMed] [Google Scholar]
  44. Vandenabeele P., Fiers W. Is amyloidogenesis during Alzheimer's disease due to an IL-1-/IL-6-mediated 'acute phase response' in the brain? Immunol Today. 1991 Jul;12(7):217–219. doi: 10.1016/0167-5699(91)90032-O. [DOI] [PubMed] [Google Scholar]
  45. Wilson L., Butcher C. J., Kellie S. Calcium ionophore A23187 induces interleukin-8 gene expression and protein secretion in human monocytic cells. FEBS Lett. 1993 Jul 5;325(3):295–298. doi: 10.1016/0014-5793(93)81092-e. [DOI] [PubMed] [Google Scholar]
  46. Yamasaki Y., Matsuo Y., Matsuura N., Onodera H., Itoyama Y., Kogure K. Transient increase of cytokine-induced neutrophil chemoattractant, a member of the interleukin-8 family, in ischemic brain areas after focal ischemia in rats. Stroke. 1995 Feb;26(2):318–323. doi: 10.1161/01.str.26.2.318. [DOI] [PubMed] [Google Scholar]
  47. Zeise M. L., Madamba S., Siggins G. R. Interleukin-1 beta increases synaptic inhibition in rat hippocampal pyramidal neurons in vitro. Regul Pept. 1992 Apr 29;39(1):1–7. doi: 10.1016/0167-0115(92)90002-c. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES