Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Ursodeoxycholic Acid Inhibits Pro-Inflammatory Repertoires, $IL-1{\beta}$ and Nitric Oxide in Rat Microglia

  • Joo, Seong-Soo (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Kang, Hee-Chul (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Won, Tae-Joon (Department of Immunology, College of Pharmacy, Chung-Ang University) ;
  • Lee, Do-ik (Department of Immunology, College of Pharmacy, Chung-Ang University)
  • Published : 2003.11.01
Download PDF
⟨ Previous Next ⟩

Abstract

Ursodeoxycholic acid (UDCA) is a non-toxic, hydrophilic bile acid in widespread clinical use mainly for acute and chronic liver disease. Recently, treatment with UDCA in hepatic graft-versus-host disease has been given in immunosuppressive therapy for improvement of the biochemical markers of cholestasis. Moreover, it has been reported that UDCA possesses immunomodulatory effects by the suppression of cytokine production. In the present study, we hypothesized that UDCA may inhibit the production of the pro-inflammatory cytokine, IL-1$\beta$, and nitric oxide (NO) in microglia. In the study, we found that 100 $\mu$ g/mL UDCA effectively inhibited these two pro-inflammatory factors at 24 hand 48 h, compared to the $A\beta$42-pretreated groups. These results were compared with the LPS+UDCA group to confirm the UDCA effect. As microglia can be activated by several stimulants, such as $A\beta$42, in Alzheimers brain and can release those inflammatory factors, the ability to inhibit or at least decrease the production of IL-1$\beta$ and NO in Alzheimers disease (AD) is essential. Using RT-PCR, ELISA and the Griess Reagent System, we therefore found that UDCA in $A\beta$42 pre-treated cultures played a significant role in suppressing the expression or the production of IL-1$\beta$ and NO. Similarly, lipopolysaccharide (LPS) did not activate microglia in the presence of UDCA. Moreover, we found that UDCA exhibits a prolonged effect on microglial cells (up to 48 h), which suggests that UDCA may play an important role in chronic cell damage due to this long effect. These results further imply that UDCA could be an important cue in suppressing the microglial activation stimulated by massive AD peptides in the AD progressing brain.

Keywords

References

  1. Banati, R. B., Gehrmann, J., Schubert, P., and Kreutzberg, G. W., Cytotoxicity of microglia. Glia, 7, 111-118 (1996) https://doi.org/10.1002/glia.440070117
  2. Bayer, T. A., Wirths, O., Majtenyl, K., Hartmann, T., Multhaup, G., Beyreuther, K., and Czech, C., Key factors in Alzheimer's disease: $\beta$-amyloid precursor protein processing, metabolism, and intraneuronal transport. Brain Pathology, 11, 1-11(2001) https://doi.org/10.1111/j.1750-3639.2001.tb00376.x
  3. Benveniste, E. N., Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action. Am. J. Physiol., 263, C1-16 (1992) https://doi.org/10.1152/ajpcell.1992.263.1.C1
  4. Beuers, U., Boyer, J. L., and Paumgartner, G., Ursodeoxycholic acid in cholestasis: Potential mechanisms of action and therapeutic applications. Hepatology, 28, 1449-1453 (1998) https://doi.org/10.1002/hep.510280601
  5. Chao, C. C., Hu, S., Molitor, T. W., Shaskan, E. C., and Peterson, P. K., Activated microglia mediated neuronal cell injury via a nitric oxide mechanism. J. Immunol., 149, 2736-2741 (1992)
  6. Dickson, D. W., Lee, S. C., Mattiace, L. A., Yen, S. H., and Brosnan, C., Microglia and cytokines in neurological disease, with special reference to AIDS and Alzheimer's disease. [Review]. Glia, 7, 75-83. (1993) https://doi.org/10.1002/glia.440070113
  7. Forloni, G., Demichelli, F., Giorgi, S., Bendotti, C., and Angeretti, N., Expression of amyloid precursor protein mRNAs in endothelial, neuronal, and glial cell: modulation by interleukin-1. Brain. Res., 16, 128-134 (1992) https://doi.org/10.1016/0169-328X(92)90202-M
  8. Giulian, D., Ameboid microglia as effectors of inflammation in the central nervous system. J. Neuroscience. Res., 18, 155-171 (1987) https://doi.org/10.1002/jnr.490180123
  9. Giulian, D., Baker, T. J., Shih, L., and Lachman, L. B., Interleukin-1 of the central nervous system is produced by ameboid microglia. J. Exp. Med., 164, 594 (1986) https://doi.org/10.1084/jem.164.2.594
  10. Hirano, F., Tanaka, H., Makino, Y., Okamoto, K., and Makino, I., Effects of ursodeoxycholic acid and chenodeoxycholic acid on major histocompatibility complex class I gene expression. J. Gastroenterol., 31(1), 55-60 (1996) https://doi.org/10.1007/BF01211187
  11. Invernizzi, P., Salzman, A. L., Szabo, C., Ueta, I., O'Connor, M., and Setchell, K. D., Ursodeoxycholate inhibits induction of NOS in human intestinal epithelial cells and in vivo. Am. J. Physiol., 273, G131-138 (1997)
  12. Jaffrey, S. R. and Snyder, S. H., Nitric oxide: a neural messenger. Annu. Rev. Cell. Dev., 11, 417-440 (1995) https://doi.org/10.1146/annurev.cb.11.110195.002221
  13. Joo, S. S., Chang, J. K., Park, J. H., Kang, H. C., and Lee, D. I., Immuno activation of lectin-conjugated praecoxin A on IL-6, IL-12 expression. Arch. Pharm. Res., 25, 954-963 (2002) https://doi.org/10.1007/BF02977019
  14. Kim, S. H., Won, S. J., Sohn, S. H., Kwon, H. J., Lee, J. Y., Park, J. H., and Gwag, B. J., Brain-derived neurotrophic factor can act as a pronecrotic factor through transcriptional and translocational activation of NADPH oxidase. J. Cell Biol., 159, 821-831 (2002) https://doi.org/10.1083/jcb.200112131
  15. Kim, W. G., Mohney, R. P., Wilson, B., Heohn, G. H., Liu, B., and Hong, J. S., Regional difference in susceptibility to lipopolysaccharide-induced neurotoxicity in the rat brain: Role of microglia. J. Neurosci., 20, 6309-6316 (2000)
  16. Liu, L., Sakaguchi, T., Cui, X., Shirai, Y., Nishimaki, T., and Hatakeyama, K., Liver regeneration enhanced by orally administered ursodesoxycholic acid is mediated by immunosuppression in partially hepatectomized rats. Am. J. Chin. Med., 30(1), 119-126 (2002) https://doi.org/10.1142/S0192415X02000132
  17. Lue, L., Rydel, R., Brigham, E .F., Yang, L., Hampek, H., Murphy, G. M., Brachova, L., Yan, S., Walker, D. G., Shen, Y., and Rogers, J., Inflammatory repertoire of Alzheimer's disease and nondemented elderly microglia in vitro. Glia, 35, 72-79 (2001) https://doi.org/10.1002/glia.1072
  18. Lue, L. F. and Walker, D. G., Modeling Alzheimer's disease immune therapy mechanisms; interaction of human postmortem microglia with antibody- opsonized amyloid beta peptide. J. Neurosci. Res., 70(4), 599-610 (2002) https://doi.org/10.1002/jnr.10422
  19. Mrak, R. E., Sheng, J. G., and Griffin, W. S. T., Glial cytokines in Alzheimers disease: review and pathogenic implication. Hum. Pathol., 26, 816-823 (1995) https://doi.org/10.1016/0046-8177(95)90001-2
  20. Paresce, D. M., Chung, H., and Maxfield., Slow degration of aggregates of the Alzheimers disease amyloid beta-protein by microglial cell. J. Biol. Chem., 272, 29390-29397 (1997) https://doi.org/10.1074/jbc.272.46.29390
  21. Paumgartner, G. and Beuers, U., Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Perspectives In Clinical Hepatology, 525-530 (2002)
  22. Possel, H., Noack, H., Putzke, J., Wolf, G., and Sies, H., Selective upregulation of inducible Nitric Oxide Synthase (iNOS) by lipopolysaccharide (LPS) and cytokines in microglia. Glia, 32, 51-59 (2000) https://doi.org/10.1002/1098-1136(200010)32:1<51::AID-GLIA50>3.0.CO;2-4
  23. Rodrigues, C. M. P., Ma, X., Kren, B. T., and Streer, C. J., A novel role for ursodeoxycholic acid in inhibiting apotosis by modulating mitochondrial membrane perturbation. J. Clin. Invest., 101(12), 2790-2799 (1998)
  24. Selkoe, D. J., The molecular pathology of Alzheimer's disease. [Review] Neuron, 6, 487-498(1991) https://doi.org/10.1016/0896-6273(91)90052-2
  25. Shoda, M., Uber die Ursodeoxycholsaure aus Barengallen und ihre physiologische Wirkung. J. Biochem., 7, 505-517 (1927) https://doi.org/10.1093/oxfordjournals.jbchem.a131239
  26. Strijbos, P. J. and Rothwell, N. J., Interleukin-1beta attenuates excitatory amino acid-induced neurodegenerstion in vitro: involvement of nerve growth factor. J. Neurosci., 153, 3468-3474 (1995)
  27. Varadarajan, S., Yatin, S., Aksenova, M., and Butterfield, D. A., Review: Alzheimers amyloid beta-peptide associated free radical oxidative stress and neurotoxicity. J. Structural Biol., 130, 184-208 (2000) https://doi.org/10.1006/jsbi.2000.4274
  28. Webster, S. D., Park, M., Fonseca, M. I., and Tenner, A. J., Structural and functional evidence for microglial expression of C1qRP, the C1q receptor that enhances phagocytosis. J. Leukocyte Biology, 67, 109-116 (2000) https://doi.org/10.1002/jlb.67.1.109
  29. Yoshikawa, M., Tsujii, T., Matsumura, K., Yamao, J., Matsumura, Y., Kubo, R., Fukui, H., and Ishizaka, S., Immunomodulatory effects of ursodeoxycholic acid on immune responses. Hepatology, 16(2), 358-364 (1992) https://doi.org/10.1002/hep.1840160213