Skip to main content

Advertisement

SpringerLink
Log in

Sodium arsenite-induced inhibition of cell proliferation is related to inhibition of IL-2 mRNA expression in mouse activated T cells

  • Inorganic Compounds
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

A proposed mechanism for the As-induced inhibition of cell proliferation is the inhibition of IL-2 secretion. However, the effects of arsenite on IL-2 mRNA expression or on the ERK pathway in activated-T cells have not yet been described. We examined the effect of arsenite on IL-2 mRNA expression, cell activation and proliferation in PHA-stimulated murine lymphocytes. Arsenite (1 and 10 μM) decreased IL-2 mRNA expression, IL-2 secretion and cell proliferation. Arsenite (10 μM) strongly inhibited ERK-phosphorylation. However, the partial inhibition (50%) of IL-2 mRNA produced by 1 μM, consistent with the effects on IL-2 secretion and cell proliferation, could not be explained by the inhibition of ERK-phosphorylation, which was not affected at this concentration. The inhibition of IL-2 mRNA expression caused by 1 μM could be associated to effects on pathways located downstream or parallel to ERK. Arsenite also decreased early activation (surface CD69+ expression) in both CD4+ and CD8+, and decreased total CD8+ count without significantly affecting CD4+, supporting that the cellular immune response mediated by cytotoxic T cells is an arsenic target. Thus, our results suggest that arsenite decreases IL-2 mRNA levels and T-cell activation and proliferation. However, further studies on the effects of arsenite on IL-2 gene transcription and IL-2 mRNA stability are needed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  • Burns LA, Munson AE (1993) Gallium arsenide selectively inhibits T cell proliferation and alters expression of CD25 (IL-2R/p55). J Pharmacol Exp Ther 265:178–186

    PubMed  CAS  Google Scholar 

  • Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987). Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of radiosensitivity. Cancer Res 15:943–946

    Google Scholar 

  • Chevalier D, Thorin E, Allen BG (2000) Simultaneous measurement of ERK, p38, and JNK MAP kinase cascades in vascular smooth muscle cells. J Pharmacol Toxicol Methods 44:429–439

    Article  PubMed  CAS  Google Scholar 

  • Chomczynski P, Sacchi N (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  PubMed  CAS  Google Scholar 

  • Cobb M, Goldsmith E (1995). How MAP kinases are regulated. J Biol Chem 270:14843–14846

    Article  PubMed  CAS  Google Scholar 

  • Crabtree G, Clipstone N (1994). Signal transmission between the plasma membrane and nucleus of T lymphocytes. Annu Rev Biochem 63:1045–1083

    Article  PubMed  CAS  Google Scholar 

  • Del Rio R, Rincón M, Layseca-Espinosa E, Fierro NA, Rosenstein Y, Pedraza-Alva G (2004) PKCtheta is required for the activation of human T lymphocytes induced by CD43 engagement. Biochem Biophys Res Commun 325:133–143

    Article  PubMed  CAS  Google Scholar 

  • Doza YN, Hall-Jackson CA, Cohen P (1998) Arsenite blocks growth factor induced activation of the MAP kinase cascade, upstream of Ras and downstream of Grb2-Sos. Oncogene 17:19–24

    Article  PubMed  CAS  Google Scholar 

  • Efrat S, Kaempfer R (1984) Control of biologically active interleukin 2 messenger RNA formation in induced human lymphocytes. Proc Natl Acad Sci USA 81:2601–2605

    Article  PubMed  CAS  Google Scholar 

  • Galicia G, Leyva R, Tenorio EP, Ostrosky-Wegman P, Saavedra R (2003) Arsenite retards proliferation of PHA-activated T cells by delaying the production and secretion of IL-2. Int Immunopharmacol 3:671–682

    Article  PubMed  CAS  Google Scholar 

  • Gao X, Xu YX, Janakiraman N, Chapman RA, Gautam C (2001) Immunomodulatory activity of resveratrol: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production. Biochem Pharmacol 62:1299–1308

    Article  PubMed  CAS  Google Scholar 

  • Germolec DR, Yoshida T, Gaido K, Wilmer JL, Simeonova PP, Kayama F, Burleson F, Dong W, Lange RW, Luster MI (1996) Arsenic induces overexpression of growth factors in human keratinocytes. Toxicol Appl Pharmacol 141:308–318

    PubMed  CAS  Google Scholar 

  • Goytia-Acevedo RC, Cebrian ME, Calderon-Aranda ES (2003) Differential effects of arsenic on intracellular free calcium levels and the proliferative response of murine mitogen-stimulated lymphocytes. Toxicology 189:235–244

    Article  PubMed  CAS  Google Scholar 

  • Hardy K, Hunt NH (2004) Effects of a redox-active agent on lymphocyte activation and early gene expression patterns. Free Radic Biol Med 37:1550–1563

    Article  PubMed  CAS  Google Scholar 

  • Hershko DD, Robb BW, Luo GJ, Hungness ES, Hasselgren PO (2003) Sodium arsenite downregulates transcriptional activity of AP-1 and CRE binding proteins in IL-1β-treated Caco-2 cells by increasing the expression of the transcriptional repressor CREMalpha. J Biol Biochem 90:627–640

    CAS  Google Scholar 

  • Hossain K, Akhand AA, Kato M, Du J, Takeda K, Wu J, Takeuchi K, Liu W, Suzuki H, Nakashima I (2000) Arsenite induces apoptosis of murine T lymphocytes through membrane raft-linked signaling for activation of c-Jun amino-terminal kinase. J Immunol 165:4290–4297

    PubMed  CAS  Google Scholar 

  • Hu Y, Jin X, Snow ET (2002) Effect of arsenic on transcription factor AP-1 and NF-κB DNA binding activity and related gene expression. Toxicol Lett 133:33–45

    Article  PubMed  CAS  Google Scholar 

  • Huang C, Ma WY, Li J, Goranson A, Dong Z (1999) Requirement of Erk, but not JNK, for arsenite-induced cell transformation. J Biol Chem 274:14595–14601

    Article  PubMed  CAS  Google Scholar 

  • Hughes-Fulford M, Sugano E, Schopper T, Li CF, Boonyaratanakornkit JB, Cogoli A (2005) Early immune response and regulation of IL-2 receptor subunitis. Cell Signal. 17:1111–1124

    Article  PubMed  CAS  Google Scholar 

  • Izquierdo M, Leevers SJ, Marshall CJ, Cantrell D (1993) p21ras copules the T cell antigen receptor to extracellular signal-regulated kinase 2 in T lymphocytes. J Exp Med 78:1199–1208

    Article  Google Scholar 

  • Koike T, Yamagishi H, Hatanaka Y, Fukushima A, Chang JW, Xia Y, Fields M, Chandler P, Iwashima M (2003) A novel ERK-dependent signaling process that regulates interleukin-2 expression in a late phase of T cell activation. J Biol Chem 278:15685–15692

    Article  PubMed  CAS  Google Scholar 

  • Li YQ, Hii CS, Der CJ, Ferrante A (1999) Direct evidence that ERK regulates the production/secretion of interleukin-2 in PHA/PMA-stimulated T lymphocytes. Immunology 96:524–528

    Article  PubMed  CAS  Google Scholar 

  • Lin S, Del Razo LM, Styblo M, Wang C, Cullen WR, Thomas DJ (2001) Arsenicals inhibit thioredoxin reductase in cultured rat hepatocytes. Chem Res Toxicol 14:305–311

    Article  PubMed  CAS  Google Scholar 

  • Luna AL, Acosta-Saavedra L, Conde P, Vera E, Cruz MB, Gómez-Muñoz A, López-Carrillo L, Cebrian ME, Calderon-Aranda ES (2003) Functional activity of Th1 and macrophages from children environmentally exposed to arsenic (abstract). Toxicol Sci 72(S1):377s

    Google Scholar 

  • Meisner NC, Hackermuller J, Uhl V, Aszodi A, Jaritz M, Auer M (2004) mRNA openers and closers: modulating AU-rich element-controlled mRNA stability by a molecular switch in mRNA secondary structure. Chem Biochem 5:1432–1447

    CAS  Google Scholar 

  • Modiano JF, Mayor J, Ball C, Chitko-McKown CG, Sakata N, Domenico HJ, Lucas JJ, Gelfand EW (1999) Quantitative and quantitative signals determine T cell cycle entry and progresión. Cell Immunol 197:19–29

    Article  PubMed  CAS  Google Scholar 

  • Musgrave BL, Watson CL, Haeryfar SM, Barnes CA, Hoski DW (2004) CD2-CD48 interactions promote interleukin-2 and interferon-gamma synthesis by stabilizing cytokine mRNA. Cell Immunol 229:1–12

    Article  PubMed  CAS  Google Scholar 

  • Ostrosky-Wegman P, Gonsebatt ME, Montero R, Vega L, Barba H, Espinosa J, Palao A, Cortinas C, Garcia-Vargas G, del Razo LM (1991) Lymphocyte proliferation kinetics and genotoxic findings in a pilot study on individuals chronically exposed to arsenic in Mexico. Mutat Res 250:477–482

    PubMed  CAS  Google Scholar 

  • Pani G, Colavitti R, Barbara B, Rosanna A, Borrello S, Galeotti T (2000) A redox signaling mechanism for density-dependent inhibition of cell growth. J Biochem Chem 275:3891–38899

    Google Scholar 

  • Petres J, Baron D, Hagedorn M (1977) Effects of arsenic cell metabolism and cell proliferation: cytogenetic and biochemical studies. Environ Health Perspect 19:223–227

    Article  PubMed  CAS  Google Scholar 

  • Seko Y, Azmi H, Fariss R, Ragheb JA (2004) Selective cytoplasmic translocation of HuR and site-specific binding to the interleukin-2 mRNA are not sufficient for CD28-mediated stabilization of the mRNA. J Biol Chem 279:33359–33367

    Article  PubMed  CAS  Google Scholar 

  • Serfling E, Bathelmas R, Pfeuffer I, Schenk B, Zarius S, Swoboda R, Mercurio F, Karin M (1989) Ubiquitous and lymphocyte-specif factors are involved in the induction of the mouse interleukin 2 gene in T lymphocytes. EMBO J 8:465–473

    PubMed  CAS  Google Scholar 

  • Snow ET (1992) Metal carcinogenesis: mechanistic implications. Pharmacol Ther 53:31–65

    Article  PubMed  CAS  Google Scholar 

  • Soto-Peña GA, Luna AL, Acosta-Saavedra L, Conde-Moo P, Lopez-Carrillo L, Cebrian ME, Bastida M, Calderon-Aranda ES, Vega L (2006) Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic. FASEB J 20:779–781

    PubMed  Google Scholar 

  • Tanaka-Kagawa T, Hanioka N, Yoshida H, Jinno H, Ando M (2003) Arsenite and arsenate activate extracellular signal-regulated kinases 1/2 by an epidermal growth factor receptor-mediated pathway in normal human keratinocytes. Br J Dermatol 149:1116–1127

    Article  PubMed  CAS  Google Scholar 

  • Tenorio EP, Saavedra R (2005) Differential effect of sodium arsenite during the activation of human CD4+ and CD8+ T lymphocytes. Int Immunopharmacol 5:1853–1869

    Article  PubMed  CAS  Google Scholar 

  • Thomas DJ, Styblo M, Lin S (2001) The cellular metabolism and systemic toxicity of arsenic. Toxicol Appl Pharmacol 176:127–144

    Article  PubMed  CAS  Google Scholar 

  • Vega L, Ostrosky-Wegman P, Fortoul TI, Diaz C, Madrid V, Saavedra R (1999) Sodium arsenite reduces proliferation of human activated T-cells by inhibition of the secretion of interleukin-2. Immunopharmacol Immunotoxicol 21:203–220

    Article  PubMed  CAS  Google Scholar 

  • Yu HS, Chang KL, Yu CL, Wu CS, Chen GS, Ho JC (1998) Defective IL-2 receptor expression in lymphocytes of patients with arsenic-induced Bowen’s disease. Arch Dermatol Res 290:681–687

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Mariano E. Cebrian for helpful discussion and critical reading of the manuscript. We appreciate the technical assistance of VH. Rosales and V. Nuñez. This work was partially supported by the Mexican Council for Science and Technology (Conacyt-34508-M and Conacyt-42297-M).

Author information

Authors and Affiliations

  1. Sección Toxicología, Centro de Investigación y de Estudios Avanzados, CINVESTAV, P.O. Box 14-740, Mexico, D.F., 07360, Mexico

    Patricia Conde, Leonor C. Acosta-Saavedra & Emma S. Calderon-Aranda

  2. Facultad de Medicina, Universidad Juarez del Estado de Durango, Gomez Palacio, Durango, 03500, Mexico

    Raquel C. Goytia-Acevedo

Authors
  1. Patricia Conde
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leonor C. Acosta-Saavedra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Raquel C. Goytia-Acevedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Emma S. Calderon-Aranda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emma S. Calderon-Aranda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Conde, P., Acosta-Saavedra, L.C., Goytia-Acevedo, R.C. et al. Sodium arsenite-induced inhibition of cell proliferation is related to inhibition of IL-2 mRNA expression in mouse activated T cells. Arch Toxicol 81, 251–259 (2007). https://doi.org/10.1007/s00204-006-0152-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-006-0152-7

Keywords

Search

Navigation