Skip to main content
Clinical and Diagnostic Laboratory Immunology logoLink to Clinical and Diagnostic Laboratory Immunology
. 1995 Sep;2(5):604–608. doi: 10.1128/cdli.2.5.604-608.1995

Tumor necrosis factor alpha upregulates human microglial cell production of interleukin-10 in vitro.

W S Sheng 1, S Hu 1, F H Kravitz 1, P K Peterson 1, C C Chao 1
PMCID: PMC170206  PMID: 8548541

Abstract

Interleukin (IL)-10 appears to play an important regulatory role in the systemic inflammatory response; however, production of IL-10 within the human central nervous system has not been described. Using cultures of human fetal microglial cells, the resident macrophages of the brain, we investigated the production and regulation of bioactive IL-10. Lipopolysaccharide stimulated acute release of tumor necrosis factor (TNF)-alpha (peak by 8 h) and delayed production of IL-10 (over a 48-h period) in microglial cell cultures. Treatment of microglial cell cultures with TNF-alpha and IL-6 resulted in a dose-dependent release of IL-10. These cytokines also induced expression of IL-10 mRNA. Treatment of microglial cell cultures with IL-10 markedly inhibited TNF-alpha and IL-6 production. These findings suggest that during inflammation within the brain, acute release of TNF-alpha and IL-6 by activated microglia could promote subsequent release of IL-10, which functions to minimize the potential neurotoxic effects of proinflammatory cytokines.

Full Text

The Full Text of this article is available as a PDF (270.2 KB).

Selected References

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

  1. Akridge R. E., Oyafuso L. K., Reed S. G. IL-10 is induced during HIV-1 infection and is capable of decreasing viral replication in human macrophages. J Immunol. 1994 Dec 15;153(12):5782–5789. [PubMed] [Google Scholar]
  2. Beutler B., Grau G. E. Tumor necrosis factor in the pathogenesis of infectious diseases. Crit Care Med. 1993 Oct;21(10 Suppl):S423–S435. [PubMed] [Google Scholar]
  3. 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]
  4. Boje K. M., Arora P. K. Microglial-produced nitric oxide and reactive nitrogen oxides mediate neuronal cell death. Brain Res. 1992 Aug 7;587(2):250–256. doi: 10.1016/0006-8993(92)91004-x. [DOI] [PubMed] [Google Scholar]
  5. Burke J. M., Roberts C. W., Hunter C. A., Murray M., Alexander J. Temporal differences in the expression of mRNA for IL-10 and IFN-gamma in the brains and spleens of C57BL/10 mice infected with Toxoplasma gondii. Parasite Immunol. 1994 Jun;16(6):305–314. doi: 10.1111/j.1365-3024.1994.tb00353.x. [DOI] [PubMed] [Google Scholar]
  6. Chao C. C., Gekker G., Hu S., Peterson P. K. Human microglial cell defense against Toxoplasma gondii. The role of cytokines. J Immunol. 1994 Feb 1;152(3):1246–1252. [PubMed] [Google Scholar]
  7. Chao C. C., Hu S., Close K., Choi C. S., Molitor T. W., Novick W. J., Peterson P. K. Cytokine release from microglia: differential inhibition by pentoxifylline and dexamethasone. J Infect Dis. 1992 Oct;166(4):847–853. doi: 10.1093/infdis/166.4.847. [DOI] [PubMed] [Google Scholar]
  8. Chao C. C., Hu S., Kravitz F. H., Tsang M., Anderson W. R., Peterson P. K. Transforming growth factor-beta protects human neurons against beta-amyloid-induced injury. Mol Chem Neuropathol. 1994 Oct-Dec;23(2-3):159–178. doi: 10.1007/BF02815409. [DOI] [PubMed] [Google Scholar]
  9. Chao C. C., Hu S., Molitor T. W., Shaskan E. G., Peterson P. K. Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J Immunol. 1992 Oct 15;149(8):2736–2741. [PubMed] [Google Scholar]
  10. Chao C. C., Hu S. Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures. Dev Neurosci. 1994;16(3-4):172–179. doi: 10.1159/000112104. [DOI] [PubMed] [Google Scholar]
  11. Chao C. C., Molitor T. W., Hu S. Neuroprotective role of IL-4 against activated microglia. J Immunol. 1993 Aug 1;151(3):1473–1481. [PubMed] [Google Scholar]
  12. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  13. Derkx B., Marchant A., Goldman M., Bijlmer R., van Deventer S. High levels of interleukin-10 during the initial phase of fulminant meningococcal septic shock. J Infect Dis. 1995 Jan;171(1):229–232. doi: 10.1093/infdis/171.1.229. [DOI] [PubMed] [Google Scholar]
  14. Dickson D. W., Mattiace L. A., Kure K., Hutchins K., Lyman W. D., Brosnan C. F. Microglia in human disease, with an emphasis on acquired immune deficiency syndrome. Lab Invest. 1991 Feb;64(2):135–156. [PubMed] [Google Scholar]
  15. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fiorentino D. F., Zlotnik A., Mosmann T. R., Howard M., O'Garra A. IL-10 inhibits cytokine production by activated macrophages. J Immunol. 1991 Dec 1;147(11):3815–3822. [PubMed] [Google Scholar]
  17. Frei K., Lins H., Schwerdel C., Fontana A. Antigen presentation in the central nervous system. The inhibitory effect of IL-10 on MHC class II expression and production of cytokines depends on the inducing signals and the type of cell analyzed. J Immunol. 1994 Mar 15;152(6):2720–2728. [PubMed] [Google Scholar]
  18. Frei K., Nadal D., Pfister H. W., Fontana A. Listeria meningitis: identification of a cerebrospinal fluid inhibitor of macrophage listericidal function as interleukin 10. J Exp Med. 1993 Oct 1;178(4):1255–1261. doi: 10.1084/jem.178.4.1255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gallo P., Sivieri S., Rinaldi L., Yan X. B., Lolli F., De Rossi A., Tavolato B. Intrathecal synthesis of interleukin-10 (IL-10) in viral and inflammatory diseases of the central nervous system. J Neurol Sci. 1994 Oct;126(1):49–53. doi: 10.1016/0022-510x(94)90093-0. [DOI] [PubMed] [Google Scholar]
  20. Glauser M. P., Zanetti G., Baumgartner J. D., Cohen J. Septic shock: pathogenesis. Lancet. 1991 Sep 21;338(8769):732–736. doi: 10.1016/0140-6736(91)91452-z. [DOI] [PubMed] [Google Scholar]
  21. Gérard C., Bruyns C., Marchant A., Abramowicz D., Vandenabeele P., Delvaux A., Fiers W., Goldman M., Velu T. Interleukin 10 reduces the release of tumor necrosis factor and prevents lethality in experimental endotoxemia. J Exp Med. 1993 Feb 1;177(2):547–550. doi: 10.1084/jem.177.2.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gómez-Jiménez J., Martín M. C., Sauri R., Segura R. M., Esteban F., Ruiz J. C., Nuvials X., Bóveda J. L., Peracaula R., Salgado A. Interleukin-10 and the monocyte/macrophage-induced inflammatory response in septic shock. J Infect Dis. 1995 Feb;171(2):472–475. doi: 10.1093/infdis/171.2.472. [DOI] [PubMed] [Google Scholar]
  23. Howard M., Muchamuel T., Andrade S., Menon S. Interleukin 10 protects mice from lethal endotoxemia. J Exp Med. 1993 Apr 1;177(4):1205–1208. doi: 10.1084/jem.177.4.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hunter C. A., Litton M. J., Remington J. S., Abrams J. S. Immunocytochemical detection of cytokines in the lymph nodes and brains of mice resistant or susceptible to toxoplasmic encephalitis. J Infect Dis. 1994 Oct;170(4):939–945. doi: 10.1093/infdis/170.4.939. [DOI] [PubMed] [Google Scholar]
  25. Kennedy M. K., Torrance D. S., Picha K. S., Mohler K. M. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J Immunol. 1992 Oct 1;149(7):2496–2505. [PubMed] [Google Scholar]
  26. Marchant A., Bruyns C., Vandenabeele P., Ducarme M., Gérard C., Delvaux A., De Groote D., Abramowicz D., Velu T., Goldman M. Interleukin-10 controls interferon-gamma and tumor necrosis factor production during experimental endotoxemia. Eur J Immunol. 1994 May;24(5):1167–1171. doi: 10.1002/eji.1830240524. [DOI] [PubMed] [Google Scholar]
  27. Marchant A., Devière J., Byl B., De Groote D., Vincent J. L., Goldman M. Interleukin-10 production during septicaemia. Lancet. 1994 Mar 19;343(8899):707–708. doi: 10.1016/s0140-6736(94)91584-9. [DOI] [PubMed] [Google Scholar]
  28. Masood R., Lunardi-Iskandar Y., Moudgil T., Zhang Y., Law R. E., Huang C. L., Puri R. K., Levine A. M., Gill P. S. IL-10 inhibits HIV-1 replication and is induced by tat. Biochem Biophys Res Commun. 1994 Jul 15;202(1):374–383. doi: 10.1006/bbrc.1994.1938. [DOI] [PubMed] [Google Scholar]
  29. O'Garra A., Stapleton G., Dhar V., Pearce M., Schumacher J., Rugo H., Barbis D., Stall A., Cupp J., Moore K. Production of cytokines by mouse B cells: B lymphomas and normal B cells produce interleukin 10. Int Immunol. 1990;2(9):821–832. doi: 10.1093/intimm/2.9.821. [DOI] [PubMed] [Google Scholar]
  30. Oswald I. P., Wynn T. A., Sher A., James S. L. Interleukin 10 inhibits macrophage microbicidal activity by blocking the endogenous production of tumor necrosis factor alpha required as a costimulatory factor for interferon gamma-induced activation. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8676–8680. doi: 10.1073/pnas.89.18.8676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Peterson P. K., Gekker G., Hu S., Schoolov Y., Balfour H. H., Jr, Chao C. C. Microglial cell upregulation of HIV-1 expression in the chronically infected promonocytic cell line U1: the role of tumor necrosis factor-alpha. J Neuroimmunol. 1992 Nov;41(1):81–87. doi: 10.1016/0165-5728(92)90198-t. [DOI] [PubMed] [Google Scholar]
  32. Pfister H. W., Fontana A., Täuber M. G., Tomasz A., Scheld W. M. Mechanisms of brain injury in bacterial meningitis: workshop summary. Clin Infect Dis. 1994 Sep;19(3):463–479. doi: 10.1093/clinids/19.3.463. [DOI] [PubMed] [Google Scholar]
  33. Reed S. G., Brownell C. E., Russo D. M., Silva J. S., Grabstein K. H., Morrissey P. J. IL-10 mediates susceptibility to Trypanosoma cruzi infection. J Immunol. 1994 Oct 1;153(7):3135–3140. [PubMed] [Google Scholar]
  34. Saville M. W., Taga K., Foli A., Broder S., Tosato G., Yarchoan R. Interleukin-10 suppresses human immunodeficiency virus-1 replication in vitro in cells of the monocyte/macrophage lineage. Blood. 1994 Jun 15;83(12):3591–3599. [PubMed] [Google Scholar]
  35. Stearman M., Southgate H. J. The use of cytokine and C-reactive protein measurements in cerebrospinal fluid during acute infective meningitis. Ann Clin Biochem. 1994 May;31(Pt 3):255–261. doi: 10.1177/000456329403100307. [DOI] [PubMed] [Google Scholar]
  36. Sáez-Llorens X., Ramilo O., Mustafa M. M., Mertsola J., McCracken G. H., Jr Molecular pathophysiology of bacterial meningitis: current concepts and therapeutic implications. J Pediatr. 1990 May;116(5):671–684. doi: 10.1016/s0022-3476(05)82647-2. [DOI] [PubMed] [Google Scholar]
  37. Tunkel A. R., Scheld W. M. Pathogenesis and pathophysiology of bacterial meningitis. Clin Microbiol Rev. 1993 Apr;6(2):118–136. doi: 10.1128/cmr.6.2.118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wang P., Wu P., Siegel M. I., Egan R. W., Billah M. M. IL-10 inhibits transcription of cytokine genes in human peripheral blood mononuclear cells. J Immunol. 1994 Jul 15;153(2):811–816. [PubMed] [Google Scholar]
  39. Wanidworanun C., Strober W. Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis. J Immunol. 1993 Dec 15;151(12):6853–6861. [PubMed] [Google Scholar]
  40. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. van der Poll T., Jansen J., Levi M., ten Cate H., ten Cate J. W., van Deventer S. J. Regulation of interleukin 10 release by tumor necrosis factor in humans and chimpanzees. J Exp Med. 1994 Nov 1;180(5):1985–1988. doi: 10.1084/jem.180.5.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Clinical and Diagnostic Laboratory Immunology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES