Skip to main content

Advertisement

SpringerLink
Log in

Inhibitory effect of citrinin on lipopolisaccharide-induced nitric oxide production by mouse macrophage cells

  • Original Paper
  • Published:
Mycotoxin Research Aims and scope Submit manuscript

Abstract

The present study evaluated the immunotoxicity of citrinin (CIT), a mycotoxin produced by several Aspergillus, Penicillium, and Monascus species. Because nitric oxide (NO), a pro-inflammatory mediator, plays an important role in the protection from pathogens, we addressed the effect of CIT on NO production by a mouse macrophage-like cell line RAW264 activated with lipopolysaccharide (LPS). LPS-induced NO release from RAW264 cells was inhibited by CIT. Moreover, the transcription and expression of inducible NO synthase (iNOS) by LPS was suppressed by CIT. These results show that CIT suppressed the LPS-induced NO production and iNOS expression, which contribute to the host protection against invading pathogens. This suggests that CIT on LPS-induced NO release may exert adverse effects in macrophages, indicating immunotoxic effects of this toxin. .

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
Fig. 5

Similar content being viewed by others

References

  • Arai M, Hibino T (1983) Tumorigenicity of citrinin in male F344 rats. Cancer Lett 17:281–287

    Article  PubMed  CAS  Google Scholar 

  • Bennett JW, Klich M (2003) Mycotoxins. Clin Microbiol Rev 16:497–516

    Article  PubMed  CAS  Google Scholar 

  • Bezbradica JS, Medzhitov R (2009) Integration of cytokine and heterologous receptor signaling pathways. Nat Immunol 10:333–339

    Article  PubMed  CAS  Google Scholar 

  • Bondy GS, Pestka JJ (2000) Immunomodulation by fungal toxins. J Toxicol Environ Health B 3:109–143

    Article  CAS  Google Scholar 

  • Boockvar KS, Granger DL, Poston RM, Maybodi M, Washington MK, Hibbs JB Jr, Kurlander RL (1994) Nitric oxide produced during murine listeriosis is protective. Infect Immun 62:1089–1100

    PubMed  CAS  Google Scholar 

  • Chang CH, Yu FY, Wu TS, Wang LT, Liu BH (2011) Mycotoxin citrinin induced cell cycle G2/M arrest and numerical chromosomal aberration associated with disruption of microtubule formation in human cells. Toxicol Sci 119:84–92

    Article  PubMed  CAS  Google Scholar 

  • Dirks W, Mittnacht S, Rentrop M, Hauser H (1989) Isolation and functional characterization of the murine interferon-β1 promoter. J Interferon Res 9:125–133

    Article  PubMed  CAS  Google Scholar 

  • El Kasmi KC, Qualls JE, Pesce JT, Smith AM, Thompson RW, Henao-Tamayo M, Basaraba RJ, König T, Schleicher U, Koo MS (2008) Toll-like receptor–induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol 9:1399–1406

    Article  PubMed  Google Scholar 

  • Ezra N, Ochoa MT, Craft N (2010) Human immunodeficiency virus and leishmaniasis. J Glob Infect Dis 2:248

    Article  PubMed  Google Scholar 

  • Hiscott J, Alper D, Cohen L, Leblanc JF, Sportza L, Wong A, Xanthoudakis V (1989) Induction of human interferon gene expression is associated with a nuclear factor that interacts with the NF-kappa B site of the human immunodeficiency virus enhancer. J Virol 63:2557–2566

    PubMed  CAS  Google Scholar 

  • Hökby E, Hult K, Gatenbeck S, Rutqvist L (1979) Ochratoxin A and citrinin in 1976 crop of barley stored on farms in Sweden. Acta Agric Scand 29:174–178

    Article  Google Scholar 

  • Jacobs AT, Ignarro LJ (2001) Lipopolysaccharide-induced expression of interferon-β mediates the timing of inducible nitric-oxide synthase induction in RAW 264.7 macrophages. J Biol Chem 276:47950–47957

    PubMed  CAS  Google Scholar 

  • Kim YM, Lee BS, Yi KY, Paik SG (1997) Upstream NF-κB site is required for the maximal expression of mouse inducible nitric oxide synthase gene in interferon-γ plus lipopolysaccharide-induced RAW 264.7 macrophages. Biochem Biophys Res Commun 236:655–660

    Article  PubMed  CAS  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  PubMed  CAS  Google Scholar 

  • Lenardo MJ, Fan CM, Maniatis T, Baltimore D (1989) The involvement of NF-kappa B in beta-interferon gene regulation reveals its role as widely inducible mediator of signal transduction. Cell 57:287

    Article  PubMed  CAS  Google Scholar 

  • Liu BH, Chi JY, Hsiao YW, Tsai KD, Lee YJ, Lin CC, Hsu SC, Yang SM, Lin TH (2010) The fungal metabolite, citrinin, inhibits lipopolysaccharide/interferon-γ-induced nitric oxide production in glomerular mesangial cells. Int Immunopharmacol 1012:1608–1615

    Article  Google Scholar 

  • Lowenstein CJ, Alley EW, Raval P, Snowman AM, Snyder SH, Russell SW, Murphy WJ (1993) Macrophage nitric oxide synthase gene: two upstream regions mediate induction by interferon gamma and lipopolysaccharide. Proc Natl Acad Sci USA 90:9730–9734

    Article  PubMed  CAS  Google Scholar 

  • Martin W, Lorkowski G, Creppy EE, Dirheimer G, Röschenthaler R (1986) Action of citrinin on bacterial chromosomal and plasmid DNA in vivo and in vitro. Appl Environ Microbiol 52:1273–1279

    PubMed  CAS  Google Scholar 

  • Marin ML, Murtha J, Dong W, Pestka JJ (1996) Effects of mycotoxins on cytokine production and proliferation in EL-4 thymoma cells. J Toxicol Environ Health 48:379–396

    Article  PubMed  CAS  Google Scholar 

  • Mayura K, Parker R, Berndt WO, Phillips TD (1984) Effect of simultaneous prenatal exposure to ochratoxin A and citrinin in the rat. J Toxicol Environ Health 13:553–561

    Article  PubMed  CAS  Google Scholar 

  • Miller BH, Fratti RA, Poschet JF, Timmins GS, Master SS, Burgos M, Marletta MA, Deretic V (2004) Mycobacteria inhibit nitric oxide synthase recruitment to phagosomes during macrophage infection. Infect Immun 72:2872–2878

    Article  PubMed  CAS  Google Scholar 

  • Murphy WJ, Muroi M, Zhang CX, Suzuki T, Russell SW (1996) Both basal and enhancer κB elements are required for full induction of the mouse inducible nitric oxide synthase gene. J Endotoxin Res 3:381–393

    CAS  Google Scholar 

  • Nelson TS, Kirby LK, Beasley JN, Johnson ZB, Ciegler A (1985) The effect of drying method and storage time on citrinin activity in corn. Poult Sci 64:464–468

    Article  PubMed  CAS  Google Scholar 

  • Osborne BG (1980) The occurrence of ochratoxin A in mouldy bread and flour. Fd Cosmet Toxicol 18:615–617

    Article  CAS  Google Scholar 

  • Pérez–Rodríguez R, Roncero C, Oliván AM, González MP, Oset–Gasque MJ (2009) Signaling mechanisms of interferon gamma induced apoptosis in chromaffin cells: involvement of nNOS, iNOS, and NFκB. J Neurochem 108:1083–1096

    Article  PubMed  Google Scholar 

  • Pestka JJ, Smolinski AT (2005) Deoxynivalenol: toxicology and potential effects on humans. J Toxicol Environ Health B 8:39

    Article  CAS  Google Scholar 

  • Sakai K, Suzuki H, Oda H, Akaike T, Azuma Y, Murakami T, Sugi K, Ito T, Ichinose H, Koyasu S (2006) Phosphoinositide 3-Kinase in Nitric Oxide Synthesis in Macrophage. J Biol Chem 281:17736–17742

    Article  PubMed  CAS  Google Scholar 

  • Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, Monahan IM, Dolganov G, Efron B, Butcher PD, Nathan C (2003) Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages Insights into the Phagosomal Environment. J Exp Med 198:693–704

    Article  PubMed  CAS  Google Scholar 

  • Scott PM, Walbeek WV, Kennedy B, Anyeti D (1972) Mycotoxins (ochhratoxin A, citrinin, and sterigmatocystin) and toxigenic fungi in grains and other agricultural products. J Agric Food Chem 20:1103

    Article  PubMed  CAS  Google Scholar 

  • Shimomura-Shimizu M, Sugiyama K, Muroi M, Tanamoto K (2005) Alachlor and carbaryl suppress lipopolysaccharide-induced iNOS expression by differentially inhibiting NF-κB activation. Biochem Biophys Res Commun 332:793–799

    Article  PubMed  CAS  Google Scholar 

  • Sugiyama K, Kinoshita M, Kamata Y, Minai Y, Sugita-Konishi Y (2011) (−)-Epigallocatechin gallate suppresses the cytotoxicity induced by trichothecene mycotoxins in mouse cultural macrophages. Mycotoxin Res 27:281–285

    Article  PubMed  CAS  Google Scholar 

  • Sugiyama K, Muroi M, Tanamoto K (2008) A novel TLR4-binding peptide that inhibits LPS-induced activation of NF-κB and in vivo toxicity. Eur J Pharmacol 594:152–156

    Article  PubMed  CAS  Google Scholar 

  • Sugiyama K, Muroi M, Tanamoto K, Nishijima M, Sugita-Konishi Y (2010) Deoxynivalenol and nivalenol inhibit lipopolysaccharide-induced nitric oxide production by mouse macrophage cells. Toxicol Lett 192:150–154

    Article  PubMed  CAS  Google Scholar 

  • Tsutsuki H, Yahiro K, Suzuki K, Suto A, Ogura K, Nagasawa S, Ihara H, Shimizu T, Nakajima H, Moss J (2012) Subtilase cytotoxin enhances E. coli survival in macrophages by suppression of nitric oxide production through the inhibition of NF-κB activation. Infect Immun 80:3939–3951

    Article  PubMed  CAS  Google Scholar 

  • Visvanathan KV, Goodbourn S (1989) Double-stranded RNA activates binding of NF-kappa B to an inducible element in the human beta-interferon promoter. EMBO J 8:1129

    PubMed  CAS  Google Scholar 

  • Xie QW, Whisnant R, Nathan C (1993) Promoter of the mouse gene encoding calcium-independent nitric oxide synthase confers inducibility by interferon gamma and bacterial lipopolysaccharide. J Exp Med 177:1779–1784

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was partly supported by the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (no. 22790421) to K. Sugiyama. The authors are grateful to Kazuhisa Nakajima and Kaho Ikeuchi for their excellent technical assistance.

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Division of Genetics and Mutagenesis, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Kei-ichi Sugiyama

  2. Laboratory of Food Environmental Science, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kitashirakawa-Oiwake-cho, Sakyo-ku, Kyoto-shi, Kyoto, 606-8502, Japan

    Rino Yamazaki & Fumito Tani

  3. Department of Applied Biological Chemistry, Faculty of Agriculture, Tamagawa University, 6-1-1 Tamagawagakuen, Machida-shi, Tokyo, 194-8610, Japan

    Mawo Kinoshita & Yuji Minai

  4. Division of Microbiology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Yoichi Kamata & Yoshiko Sugita-Konishi

Authors
  1. Kei-ichi Sugiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rino Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mawo Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoichi Kamata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fumito Tani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuji Minai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshiko Sugita-Konishi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kei-ichi Sugiyama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sugiyama, Ki., Yamazaki, R., Kinoshita, M. et al. Inhibitory effect of citrinin on lipopolisaccharide-induced nitric oxide production by mouse macrophage cells. Mycotoxin Res 29, 229–234 (2013). https://doi.org/10.1007/s12550-013-0175-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12550-013-0175-x

Keywords

Search

Navigation