, Volume 23, Issue 4, pp 669–680 | Cite as

Exposure to lanthanum compound diminishes LPS-induced inflammation-associated gene expression: involvements of PKC and NF-κB signaling pathways

  • Fei Guo
  • Yuanlei Lou
  • Nianhua Feng
  • Guohui Li
  • An Xie
  • Xueming Huang
  • Yang Wang


Lanthanum chloride, a rare earth compound, possesses antibacterial and cellular immunity regulating properties. However, the underlying molecular mechanisms remain largely unknown. In this study, we examined the effects of lanthanum chloride on the production of nitric oxide (NO) and tumor necrosis factor-α (TNF-α), the expression of inducible NO synthase (iNOS) and TNF-α in RAW 264.7 cells, a mouse macrophage cell line. We found that the LPS-elicited excessive production of NO and TNF-α in RAW 264.7 cells was inhibited significantly in the presence of lanthanum chloride, and the attenuation of iNOS and TNF-α occurred at mRNA level. Furthermore, the possible signaling components affected by lanthanum chloride in the pathway that lead to LPS-induced iNOS and TNF-α expression were explored. The results indicated the involvements of PKC/Ca2+ and NF-κB in the attenuation of NO and pro-inflammatory cytokine production by lanthanum chloride. Our observations suggest a possible therapeutic application of this agent for treating inflammatory diseases.


Lanthanum chloride Inducible nitric oxide synthase (iNOS) Tumor necrosis factor-α (TNF-α) Nuclear factor-κ B (NF-κ B) Protein kinase C (PKC) 



The work was supported by the National Natural Science Foundation of China (30660182, 30960405), Natural Science Foundation of Jiangxi Province (2007GZY1132) and Program for Innovative Research Team of Nanchang University.


  1. Baeuerle PA (1998) IkappaB-NF-kappaB structures: at the interface of inflammation control. Cell 95(6):729–731CrossRefPubMedGoogle Scholar
  2. Chang HT, Huang CC, Cheng HH, Wang JL, Lin KL, Hsu PT, Tsai JY, Liao WC, Lu YC, Huang JK, Jan CR (2008a) Mechanisms of AM404-induced [Ca(2+)](i) rise and death in human osteosarcoma cells. Toxicol Lett 179(1):53–58CrossRefPubMedGoogle Scholar
  3. Chang WC, Di Capite J, Singaravelu K, Nelson C, Halse V, Parekh AB (2008b) Local Ca2+ influx through Ca2+ release-activated Ca2+ (CRAC) channels stimulates production of an intracellular messenger and an intercellular pro-inflammatory signal. J Biol Chem 283(8):4622–4631CrossRefPubMedGoogle Scholar
  4. Chen CC, Wang JK (1999) p38 but not p44/42 mitogen-activated protein kinase is required for nitric oxide synthase induction mediated by lipopolysaccharide in RAW 264.7 macrophages. Mol Pharmacol 55(3):481–488PubMedGoogle Scholar
  5. Chen F, Sun SC, Kuh DC, Gaydos LJ, Demers LM (1995) Essential role of NF-kappa B activation in silica-induced inflammatory mediator production in macrophages. Biochem Biophys Res Commun 214(3):985–992CrossRefPubMedGoogle Scholar
  6. Chen C, Chen YH, Lin WW (1999) Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide-induced iNOS and COX-2 expression in J774 macrophages. Immunology 97(1):124–129CrossRefPubMedGoogle Scholar
  7. Chiang SS, Chen JB, Yang WC (2005) Lanthanum carbonate (Fosrenol) efficacy and tolerability in the treatment of hyperphosphatemic patients with end-stage renal disease. Clin Nephrol 63(6):461–470PubMedGoogle Scholar
  8. Choi DY, Toledo-Aral JJ, Segal R, Halegoua S (2001) Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression. Mol Cell Biol 21(8):2695–2705CrossRefPubMedGoogle Scholar
  9. Dai J, Li CL, Zhang YZ, Xiao Q, Lei KL, Liu Y (2008a) Bioenergetic investigation of the effects of La(III) and Ca(II) on the metabolic activity of Tetrahymena thermophila BF5. Biol Trace Elem Res 122(2):148–156CrossRefPubMedGoogle Scholar
  10. Dai J, Zhang YZ, Liu Y, Li QG (2008b) Microcalorimetric study of the effect of Ce(III) on metabolic activity of mitochondria isolated from indice rice 9311. Chem Biodivers 5(7):1321–1326CrossRefPubMedGoogle Scholar
  11. De Broe ME (2008) Can the risk of gadolinium be extrapolated to lanthanum? Semin Dial 21(2):142–144CrossRefPubMedGoogle Scholar
  12. de Gracia CG (2001) An open study comparing topical silver sulfadiazine and topical silver sulfadiazine-cerium nitrate in the treatment of moderate and severe burns. Burns 27(1):67–74CrossRefPubMedGoogle Scholar
  13. Deveci M, Eski M, Sengezer M, Kisa U (2000) Effects of cerium nitrate bathing and prompt burn wound excision on IL-6 and TNF-alpha levels in burned rats. Burns 26(1):41–45CrossRefPubMedGoogle Scholar
  14. Fujii Y, Goldberg P, Hussain SN (1998) Contribution of macrophages to pulmonary nitric oxide production in septic shock. Am J Respir Crit Care Med 157(5 Pt 1):1645–1651PubMedGoogle Scholar
  15. Ghosh S, Karin M (2002) Missing pieces in the NF-kappaB puzzle. Cell 109(Suppl):S81–S96CrossRefPubMedGoogle Scholar
  16. Hadjiiski OG, Lesseva MI (1999) Comparison of four drugs for local treatment of burn wounds. Eur J Emerg Med 6(1):41–47PubMedGoogle Scholar
  17. Hambleton J, McMahon M, DeFranco AL (1995) Activation of Raf-1 and mitogen-activated protein kinase in murine macrophages partially mimics lipopolysaccharide-induced signaling events. J Exp Med 182(1):147–154CrossRefPubMedGoogle Scholar
  18. Hofmann J (1997) The potential for isoenzyme-selective modulation of protein kinase C. Faseb J 11(8):649–669PubMedGoogle Scholar
  19. Hu J, Yu S, Yang X, Wang K, Qian Z (2006) Lanthanum induces extracellular signal-regulated kinase phosphorylation through different mechanisms in HeLa cells and NIH 3T3 cells. Biometals 19(1):13–18CrossRefPubMedGoogle Scholar
  20. Jeon KI, Byun MS, Jue DM (2003) Gold compound auranofin inhibits IkappaB kinase (IKK) by modifying Cys-179 of IKKbeta subunit. Exp Mol Med 35(2):61–66PubMedGoogle Scholar
  21. Kao JP, Harootunian AT, Tsien RY (1989) Photochemically generated cytosolic calcium pulses and their detection by fluo-3. J Biol Chem 264(14):8179–8184PubMedGoogle Scholar
  22. Lallena MJ, Diaz-Meco MT, Bren G, Paya CV, Moscat J (1999) Activation of IkappaB kinase beta by protein kinase C isoforms. Mol Cell Biol 19(3):2180–2188PubMedGoogle Scholar
  23. Letari O, Nicosia S, Chiavaroli C, Vacher P, Schlegel W (1991) Activation by bacterial lipopolysaccharide causes changes in the cytosolic free calcium concentration in single peritoneal macrophages. J Immunol 147(3):980–983PubMedGoogle Scholar
  24. Lewis JB, Wataha JC, McCloud V, Lockwood PE, Messer RL, Tseng WY (2005) Au(III), Pd(II), Ni(II), and Hg(II) alter NF kappa B signaling in THP1 monocytic cells. J Biomed Mater Res A 74(3):474–481PubMedGoogle Scholar
  25. Li S, Huang F, Feng Q, Liu J, Fan S, McKenna T (1998) Overexpression of protein kinase C alpha enhances lipopolysaccharide-induced nitric oxide formation in vascular smooth muscle cells. J Cell Physiol 176(2):402–411CrossRefPubMedGoogle Scholar
  26. Lin MQ, Chang ZL (1996) LPS and PMA induced PKC-alpha and PKC-epsilon activation and translocation in murine peritoneal macrophages. Shi Yan Sheng Wu Xue Bao 29(4):429–434PubMedGoogle Scholar
  27. Manolov I, Raleva S, Genova P, Savov A, Froloshka L, Dundarova D, Argirova R (2006) Antihuman immunodeficiency virus type 1 (HIV-1) activity of rare earth metal complexes of 4-hydroxycoumarins in cell culture. Bioinorg Chem Appl 2006:71938Google Scholar
  28. Moscat J, Diaz-Meco MT, Rennert P (2003) NF-kappaB activation by protein kinase C isoforms and B-cell function. EMBO Rep 4(1):31–36CrossRefPubMedGoogle Scholar
  29. Nahrevanian H, Dascombe MJ (2002) Expression of inducible nitric oxide synthase (iNOS) mRNA in target organs of lethal and non-lethal strains of murine malaria. Parasite Immunol 24(9–10):471–478CrossRefPubMedGoogle Scholar
  30. Nelson DE, Ihekwaba AE, Elliott M, Johnson JR, Gibney CA, Foreman BE, Nelson G, See V, Horton CA, Spiller DG, Edwards SW, McDowell HP, Unitt JF, Sullivan E, Grimley R, Benson N, Broomhead D, Kell DB, White MR (2004) Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science 306(5696):704–708CrossRefPubMedGoogle Scholar
  31. Ogata N, Yamamoto H, Kugiyama K, Yasue H, Miyamoto E (2000) Involvement of protein kinase C in superoxide anion-induced activation of nuclear factor-kappa B in human endothelial cells. Cardiovasc Res 45(2):513–521CrossRefPubMedGoogle Scholar
  32. Oh PS, Lee SJ, Lim KT (2007) Glycoprotein isolated from Rhus verniciflua Stokes inhibits inflammation-related protein and nitric oxide production in LPS-stimulated RAW 264.7 cells. Biol Pharm Bull 30(1):111–116CrossRefPubMedGoogle Scholar
  33. Parker PJ, Murray-Rust J (2004) PKC at a glance. J Cell Sci 117(Pt 2):131–132CrossRefPubMedGoogle Scholar
  34. Qin JF, Chen XY, Li ZX (2002) Biological effect of rare earth element. Guang Dong Wei Liang Yuan Su Ke Xue 9(5):1–10Google Scholar
  35. Roland CR, Naziruddin B, Mohanakumar T, Flye MW (1996) Gadolinium chloride inhibits Kupffer cell nitric oxide synthase (iNOS) induction. J Leukoc Biol 60(4):487–492PubMedGoogle Scholar
  36. Sanghera JS, Weinstein SL, Aluwalia M, Girn J, Pelech SL (1996) Activation of multiple proline-directed kinases by bacterial lipopolysaccharide in murine macrophages. J Immunol 156(11):4457–4465PubMedGoogle Scholar
  37. Severn A, Wakelam M, Liew F (1992) The role of protein kinase C in the induction of nitric oxide synthesis by murine macrophages. Biochem Biophys Res Commun 188(3):997–1002CrossRefPubMedGoogle Scholar
  38. Sharma RK, Garg BS, Kurosaki H, Goto M, Otsuka M, Yamamoto T, Inoue J (2000) Aurine tricarboxylic acid, a potent metal-chelating inhibitor of NFkappaB-DNA binding. Bioorg Med Chem 8(7):1819–1823CrossRefPubMedGoogle Scholar
  39. Shigematsu T (2008) Lanthanum carbonate effectively controls serum phosphate without affecting serum calcium levels in patients undergoing hemodialysis. Ther Apher Dial 12(1):55–61CrossRefPubMedGoogle Scholar
  40. Spitaler M, Cantrell DA (2004) Protein kinase C and beyond. Nat Immunol 5(8):785–790CrossRefPubMedGoogle Scholar
  41. Steffan NM, Bren GD, Frantz B, Tocci MJ, O’Neill EA, Paya CV (1995) Regulation of IkB alpha phosphorylation by PKC- and Ca(2+)-dependent signal transduction pathways. J Immunol 155(10):4685–4691PubMedGoogle Scholar
  42. Sudhandiran G, Shaha C (2003) Antimonial-induced increase in intracellular Ca2 + through non-selective cation channels in the host and the parasite is responsible for apoptosis of intracellular Leishmania donovani amastigotes. J Biol Chem 278(27):25120–25132CrossRefPubMedGoogle Scholar
  43. Trushin SA, Pennington KN, Carmona EM, Asin S, Savoy DN, Billadeau DD, Paya CV (2003) Protein kinase Calpha (PKCalpha) acts upstream of PKCtheta to activate IkappaB kinase and NF-kappaB in T lymphocytes. Mol Cell Biol 23(19):7068–7081CrossRefPubMedGoogle Scholar
  44. Valdes JA, Hidalgo J, Galaz JL, Puentes N, Silva M, Jaimovich E, Carrasco MA (2007) NF-kappaB activation by depolarization of skeletal muscle cells depends on ryanodine and IP3 receptor-mediated calcium signals. Am J Physiol Cell Physiol 292(5):C1960–C1970CrossRefPubMedGoogle Scholar
  45. Wang Y, Guo F, Hu F, Wang G, Li G (2004) Lanthanum inhibited the binding of LPS with monocyte and CD 14 expression upregulation. Cell Mol Immunol 1(5):392–394PubMedGoogle Scholar
  46. Wolfs TG, Buurman WA, van Schadewijk A, de Vries B, Daemen MA, Hiemstra PS, van ‘t Veer C (2002) In vivo expression of Toll-like receptor 2 and 4 by renal epithelial cells: IFN-gamma and TNF-alpha mediated up-regulation during inflammation. J Immunol 168(3):1286–1293PubMedGoogle Scholar
  47. Xie QW, Kashiwabara Y, Nathan C (1994) Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase. J Biol Chem 269(7):4705–4708PubMedGoogle Scholar
  48. Zhang P, Martin M, Michalek S, Katz J (2005) Role of mitogen-activated protein kinases and NF-κB in the regulation of proinflammatory and anti-inflammatory cytokines by Porphyromonas gingivalis. Hemagglutinin B Infect Immun 73(7):3990–3998CrossRefGoogle Scholar
  49. Zhong H, SuYang H, Erdjument-Bromage H, Tempst P, Ghosh S (1997) The transcriptional activity of NF-kappaB is regulated by the IkappaB-associated PKAc subunit through a cyclic AMP-independent mechanism. Cell 89(3):413–424CrossRefPubMedGoogle Scholar
  50. Zhu Y, Gu ZL, Liang ZQ, Zhang HL, Qin ZH (2006) Prostaglandin A1 inhibits increases in intracellular calcium concentration, TXA(2) production and platelet activation. Acta Pharmacol Sin 27(5):549–554CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Fei Guo
    • 1
  • Yuanlei Lou
    • 2
  • Nianhua Feng
    • 2
  • Guohui Li
    • 1
  • An Xie
    • 2
  • Xueming Huang
    • 2
  • Yang Wang
    • 2
  1. 1.Burns Institute, The First Affiliated Hospital of Nanchang UniversityNanchangPeople’s Republic of China
  2. 2.Institute of Urology, The First Affiliated Hospital of Nanchang UniversityNanchangPeople’s Republic of China

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