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Transcellular signalling pathways and TNF-α release involved in formation of reactive oxygen species in rat alveolar macrophages exposed to tert-butylcyclohexane

  • Molecular Toxicology
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Abstract

In the present work, the effects of aliphatic (n-nonane and n-decane), alicyclic (1,2,4-trimethylcyclohexane and tert-butylcyclohexane, t-BCH) and aromatic (trimethylbenzene and tert-butylbenzene) hydrocarbon solvents on formation of reactive oxygen species (ROS) and the proinflammatory cytokine TNF-α in rat alveolar macrophages (AM) have been investigated. Formation of ROS was assessed by monitoring oxidation of 2′,7′-dichlorofluorescin to 2′,7′-dichlorofluorescein (DCF), and the proinflammatory cytokine tumour necrosis factor α (TNF-α) was detected using an enzyme-linked immunosorbent assay. DCF fluorescence was elevated in a concentration-dependent manner by the alicyclic hydrocarbons. The involvement of transcellular signalling pathways in the production of ROS by t-BCH, the most active compound, was elucidated by use of specific inhibitors. Preincubation of the AM with the mitogen-activated protein kinase (ERK 1/2) inhibitor U0126, the protein kinase C inhibitor bisindolylmaleimide, the superoxide dismutase inhibitor diethyldithiocarbamate, and the iron ion chelating agent deferoxamine reduced the DCF fluorescence significantly. t-BCH gave an increase in TNF-α release. Further, nitric oxide production measured by a modified Griess method, and intracellular calcium concentration measured by fura-2, were increased in the rat AM after exposure to t-BCH.

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References

  • Babior BM (1999) NADPH oxidase: an update. Blood 93:1464–1476

    CAS  PubMed  Google Scholar 

  • Bit RA, Davis PD, Elliott LH, Harris W, Hill CH, Keech E, Kumar H, Lawton G, Maw A, Nixon JS, Vesey DR, Wadsworth J, Wilkinson SE (1993) Inhibitors of protein kinase C. 3. Potent and highly selective bisindolylmaleimides by conformational restrictions. J Med Chem 36:21–29

    CAS  PubMed  Google Scholar 

  • Doelman CJ, Bast A (1990) Oxygen radicals in lung pathology. Free Radic Biol Med 9:381–400

    Article  CAS  PubMed  Google Scholar 

  • Dreiem A, Myhre O, Fonnum F (2002) Relationship between Lipophilicity of C6–10 hydrocarbon solvents and their ROS-inducing potency in rat cerebellar granule cells. Neurotoxicology 103:1–9

    Google Scholar 

  • Duncia JV, Santella JB, Higley CA, Pitts WJ, Wityak J, Frietze WE, Rankin FW, Sun JH, Earl RA, Tabaka AC, Teleha CA, Blom KF, Favata MF, Manos EJ, Daulerio AJ, Stradley DA, Horiuchi K, Copeland RA, Scherle PA, Trzaskos JM, Magolda RL, Trainor GL, Wexler RR, Hobbs FW, Olson RE (1998) MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett 8:2839–2844

    CAS  PubMed  Google Scholar 

  • Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273:18623–18632

    CAS  PubMed  Google Scholar 

  • Fink MP (2002) Role of reactive oxygen and nitrogen species in acute respiratory distress syndrome. Curr Opin Crit Care 8:6–11

    Article  PubMed  Google Scholar 

  • Foster JR (2001) The functions of cytokines and their uses in toxicology. Int J Exp Pathol 82:171–192

    Article  CAS  PubMed  Google Scholar 

  • Gaston B, Drazen JM, Loscalzo J, Stamler JS (1994) The biology of nitrogen oxides in the airways. Am J Respir Crit Care Med 149:538–551

    CAS  PubMed  Google Scholar 

  • Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450

    PubMed  Google Scholar 

  • Guy GR, Chua SP, Wong NS, Ng SB, Tan YH (1991) Interleukin 1 and tumor necrosis factor activate common multiple protein kinases in human fibroblasts. J Biol Chem 266:14343–14352

    CAS  PubMed  Google Scholar 

  • Halliwell B, Gutteridge JM (1999) Free radicals in biology and medicine. Clarendon Press, Oxford

  • Hetland RB, Myhre O, Låg M, Hongve D, Schwarze PE, Refsnes M (2001) Importance of soluble metals and reactive oxygen species for cytokine release induced by mineral particles. Toxicology 165:133–144

    Article  CAS  PubMed  Google Scholar 

  • Jacobson PB, Kuchera SL, Metz A, Schachtele C, Imre K, Schrier DJ (1995) Anti-inflammatory properties of Go 6850: a selective inhibitor of protein kinase C. J Pharmacol Exp Ther 275:995–1002

    CAS  PubMed  Google Scholar 

  • Kessels GC, Krause KH, Verhoeven AJ (1993) Protein kinase C activity is not involved in N-formylmethionyl-leucyl-phenylalanine-induced phospholipase D activation in human neutrophils, but is essential for concomitant NADPH oxidase activation: studies with a staurosporine analogue with improved selectivity for protein kinase C. Biochem J 292:781–785

    CAS  PubMed  Google Scholar 

  • Laskin DL, Pendino KJ (1995) Macrophages and inflammatory mediators in tissue injury. Annu Rev Pharmacol Toxicol 35:655–677

    CAS  PubMed  Google Scholar 

  • Maher JJ (1999) Cytokines: overview. Semin Liver Dis 18:109–115

    Google Scholar 

  • Miranda KM, Espey MG, Wink DA (2001) A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 5:62–71

    Article  CAS  PubMed  Google Scholar 

  • Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142

    CAS  PubMed  Google Scholar 

  • Morel F, Doussiere J, Vignais PV (1991) The superoxide-generating oxidase of phagocytic cells. Physiological, molecular and pathological aspects. Eur J Biochem 201:523–546

    CAS  PubMed  Google Scholar 

  • Myhre O, Vestad TA, Sagstuen E, Aarnes H, Fonnum F (2000) The effects of aliphatic (n-nonane), naphthenic (1,2,4-trimethylcyclohexane) and aromatic (1,2,4-trimethylbenzene) hydrocarbons on respiratory burst in human neutrophil granulocytes. Toxicol Appl Pharmacol 167:222–230

    Article  CAS  PubMed  Google Scholar 

  • Myhre O, Andersen JM, Aarnes H, Fonnum F (2003) Commentary: evaluation of the probes 2′,7′-dichlorofluorescin, luminol and lucigenin as Indicators of reactive species formation. Biochem Pharmacol 65:1575–1582

    Article  CAS  PubMed  Google Scholar 

  • Nathan CF (1987) Secretory products of macrophages. J Clin Invest 79:319–326

    CAS  PubMed  Google Scholar 

  • Nathan C, Xie Q-W (1994) Regulation of biosynthesis of nitric oxide. J Biol Chem 269:13725–13728

    CAS  PubMed  Google Scholar 

  • Nisimoto Y, Motalebi S, Han CH, Lambeth D (1999) The p67phox activation domain regulates electron flow from NADPH to flavin in flavocytochrome b558. J Biol Chem 274:22999–23005

    Article  CAS  PubMed  Google Scholar 

  • Ogino K, Oka S, Matsuura S (1987) Ulcer formation in rat stomach with diethyldithiocarbamate. J Clin Biochem Nutr 3:189–193

    CAS  Google Scholar 

  • Robaye B, Hepburn A, Lecocq R, Fiers W, Boeynaems JM, Dumont JE (1989) Tumor necrosis factor-α induces the phosphorylation of 28 kDa stress proteins in endothelial cells: possible role in protection against cytotoxicity? Biochem Biophys Res Commun 163:301–308

    CAS  PubMed  Google Scholar 

  • Sadler KL, Badwey JA (1988) Second messengers involved in superoxide production by neutrophils. Function and metabolism. Hematol Oncol Clin North Am 2:185–200

    CAS  Google Scholar 

  • Suleiman SA (1987) Petroleum hydrocarbon toxicity in vitro: effect of n-alkanes, benzene and toluene on pulmonary alveolar macrophages and lysosomal enzymes of the lung. Arch Toxicol 59:402–407

    CAS  PubMed  Google Scholar 

  • Toullec D, Pianetti P, Coste H, Bellevergue P, Grand-Perret T, Ajakane M, Baudet V, Boissin P, Boursier E, Loriolle F, Duhamel L, Charon D, Kirilovsky J (1991) The bisindolylmaleimide GF 109203X is a potent and selective inhibitor of protein kinase C. J Biol Chem 266:15771–15781

    CAS  PubMed  Google Scholar 

  • Tsien RY, Rink TJ, Poenie M (1985) Measurement of cytosolic free Ca2+ in individual small cells using fluorescence microscopy with dual excitation wavelength. Cell Calcium 6:145–157

    CAS  PubMed  Google Scholar 

  • Van Lint J, Agostinis P, Vandevoorde V, Haegeman G, Fiers W, Merlevede W, Vandenheede JR (1992) Tumor necrosis factor stimulates multiple serine/threonine protein kinases in Swiss 3T3 and L929 cells. Implication of casein kinase-2 and extracellular signal-regulated kinases in the tumor necrosis factor signal transduction pathway. J Biol Chem 267:25916–25921

    PubMed  Google Scholar 

  • Vietor I, Schwenger P, Li W, Schlessinger J, Vilcek J (1993) Tumor necrosis factor-induced activation and increased tyrosine phosphorylation of mitogen-activated protein (MAP) kinase in human fibroblasts. J Biol Chem 268:18994–18999

    CAS  PubMed  Google Scholar 

  • Vilcek J, Lee TH (1991) Minireview: tumor necrosis factor: new insights into the molecular mechanisms of its multiple actions. J Biol Chem 226:7313–7316

    Google Scholar 

  • Ward SG, Parry RV, Matthews J (1997) A p38 MAP kinase inhibitor SB203580 inhibits CD28-dependent T cell proliferation and IL-2 production. Biochem Soc Trans 25:304S

    CAS  PubMed  Google Scholar 

  • Zahlsen K, Nilsen AM, Eide I, Nilsen OG (1990) Accumulation and distribution of aliphatic (n-nonane), aromatic (1,2,4- trimethylbenzene) and naphthenic (1,2,4-trimethylcyclohexane) hydrocarbons in the rat after repeated inhalation. Pharmacol Toxicol 67:436–440

    CAS  PubMed  Google Scholar 

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Acknowledgements

This investigation is carried out in accordance with the law and regulations in Norway.

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Author notes

  1. Oddvar Myhre

    Present address: Department of Regulatory Toxicology, Amersham Health AS, Nycoveien 2, PO Box 4220 Nydalen, 0401, Oslo, Norway

Authors and Affiliations

  1. VISTA (The Norwegian Academy of Science and Letters/Statoil), PO Box 25, 2027, Kjeller, Norway

    Berit Bjugan Aam, Oddvar Myhre & Frode Fonnum

  2. Division for Protection and Materiel, Norwegian Defence Research Establishment, PO Box 25, 2027, Kjeller, Norway

    Oddvar Myhre & Frode Fonnum

Authors
  1. Berit Bjugan Aam
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  2. Oddvar Myhre
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  3. Frode Fonnum
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Correspondence to Frode Fonnum.

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Aam, B.B., Myhre, O. & Fonnum, F. Transcellular signalling pathways and TNF-α release involved in formation of reactive oxygen species in rat alveolar macrophages exposed to tert-butylcyclohexane. Arch Toxicol 77, 678–684 (2003). https://doi.org/10.1007/s00204-003-0507-2

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  • DOI: https://doi.org/10.1007/s00204-003-0507-2

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