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IL-6 receptor-mediated lung Th2 cytokine networking in silica-induced pulmonary fibrosis

  • Organ Toxicity and Mechanisms
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Abstract

Pulmonary silicosis is a deadly disease which kills thousands of people every year worldwide. The disease initially develops as an inflammatory response with recruitment of inflammatory cells into the lung controlled by multiple cytokines. The question whether these cytokines exert biological functions through signal transducing pathway remains unanswered along with the potential role of interleukin-6 receptor α (IL-6Rα) in regulating inflammatory cytokines. We aimed to assess the status of signal transducers and activator of transcription (Stat3), suppressor of cytokine signalling 3(Socs3) and inflammatory cytokines in airways of silica-exposed mice, and their relationship with IL-6Rα. Silica-exposed and silica-exposed IL-6Rα gene knockdown Balb/c mice were used in the study. Lung function was measured by plethysmography, mRNA expression of cytokines and signal molecules by qRT2-PCR and lung architecture by histopathology; T helper cell-type 2 (Th2) cytokines in broncho-alveolar lavage fluids were evaluated by ELISA and hydroxyproline in lung by colorimetry. Elevated levels of collagen deposition, signs of lung fibrosis, infiltration of inflammatory cells and presence of exfoliated mucosa in the lung of silica-exposed mice with concurrent increase in methacholine-induced specific resistance of airways were observed on day 60 post-exposure. In parallel, heightened expression of Th2 cytokines (IL-4, IL-5, IL-6) and signal molecules (Stat3 and Socs3) were observed in the airways of silica-exposed mice. Th1 (IL-1β and TNF-α) cytokines are underexpressed in majority of the airways tissues of silica-exposed mice. Silencing IL-6Rα in lung of silica-exposed mice down regulated the hypermorphic mRNA pool of potential Th2 cytokines and signal molecules. Hypermorphic expression of Th2 cytokines and signal molecules in airways of silica-exposed mice are mediated through IL-6Rα.

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References

  • Alam R (1997) Updates on cells and cytokines: chemokines in allergic inflammation. J Allergy Clin Immunol 99:273–277

    Article  CAS  PubMed  Google Scholar 

  • Auernhammer CI, Bourquet C, Melmed S (1999) Autoregulation of pituitary corticotroph Socs-3 expression: characterisation of murine Socs 3 promoter. Proc Natl Acad Sci USA 96:6964–6969

    Article  CAS  PubMed  Google Scholar 

  • Barrett EG, Johnston C, Oberdorster G, Finkelstein JN (1999) Antioxidant treatment attenuates cytokine and chemokine levels in murine macrophages following silica exposure. Toxicol Appl Pharmacol 158:211–220

    Article  CAS  PubMed  Google Scholar 

  • Boulanger MJ, Chow DC, Brevnova EE, Garcia KC (2003) Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science 300:2101–2104

    Article  CAS  PubMed  Google Scholar 

  • Broide DH, Lotz M, Cuomo AJ, Coburn DA, Federman EC, Wasserman SI (1992) Cytokines in symptomatic asthma airways. J Allergy Clin Immunol 89:958–967

    Article  CAS  PubMed  Google Scholar 

  • Castranova V, Huffman L, Judy DJ, Bylander JE, Lapp LN, Weber SL, Blackford JA, Dey RD (1998) Enhancement of nitric oxide production by pulmonary cells following silica exposure. Environ Health Perspect 106:1165–1169

    Article  CAS  PubMed  Google Scholar 

  • Chung KF (2001) Cytokines in chronic obstructive pulmonary disease. Eur Respir J 18:50s–59s

    Article  CAS  Google Scholar 

  • Churchyard DJ, Ehrlich R, teWaterNaude JM, Pemba L, Dekker K, Vermeijs M, White N, Myers J (2004) Silicosis prevalence and exposure-response relations in South African goldminers. Occup Environ Med 61:811–816

    Article  CAS  PubMed  Google Scholar 

  • Corbett EL, Churchyard GJ, Clayton T, Herselman P, Williams B, Hayes R, Mulder D, De Cock KM (1999) Risk factors for pulmonary mycobacterial disease in South African gold miners. A case–control study. Am J Respir Crit Care Med 159:94–99

    CAS  PubMed  Google Scholar 

  • Daniel LN, Mao Y, Williams AO, Saffiotti U (1995) Direct interaction between crystalline silica and DNA—a proposed model for silica carcinogenesis. Scand J Work Environ Health 21:22–26

    CAS  PubMed  Google Scholar 

  • Driscoll KE, Carter JM, Howard BW, Hassenbein D, Janssen YM, Mossman BT (1998) Crocidolite activates NF-κB and MIP-2 gene expression in rat alveolar epithelial cells. Role of mitochondrial-derived oxidants. Environ Health Perspect 106:1171–1174

    Article  CAS  PubMed  Google Scholar 

  • Dubois CM, Bissonnette E, Rola-Pleszczynski M (1989) Asbestos fibers and silica particles stimulate rat alveolar macrophages to release tumor necrosis factor: autoregulatory role of leukotriene B4. Am Rev Respir Dis 139:1257–1264

    CAS  PubMed  Google Scholar 

  • Dunne P (2009) Silicosis: the disease that time forgot. [Available: http://arch/design.com/blog/?p=3848]

  • Fenton MJ (2003) Cytokines and lung disease: introduction and overview. Cytokine Growth Factor Rev 14:463–465

    Article  CAS  Google Scholar 

  • Gao H, Guo RF, Speyer CL, Reuben J, Neff TA, Hoesel LM, Riedemann NC, McClintock SD, Sarma JV, Van Rooijen N, Zetoune FS, Ward PA (2004) Stat3 activation in acute lung injury. J Immunol 172:7703–7712

    CAS  PubMed  Google Scholar 

  • Goodman MG, Chenoweth DE, Weigle WO (1982) Induction of interleukin 1 secretion and enhancement of humoral immunity by binding of human C5a to macrophage surface C5a receptors. J Exp Med 156:912–917

    Article  CAS  PubMed  Google Scholar 

  • Gosset P, Lassalle P, Vanhee D, Wallaert B, Aerts C, Voisin C, Tonnel AB (1991) Production of tumor necrosis factor-α and interleukin-6 by human alveolar macrophages exposed in vitro to coal mine dust. Am J Respir Cell Mol Biol 5:431–436

    CAS  PubMed  Google Scholar 

  • Hnizdo E, Murray J (1998) Risk of pulmonary tuberculosis relative to silicosis and exposure to silica dust in South African gold miners. Occup Environ Med 55:496–502

    Article  CAS  PubMed  Google Scholar 

  • Hnizdo E, Vallyathan V (2003) Chronic obstructive pulmonary disease due to occupational exposure to silica dust: a review of epidemiological and pathological evidence. Occup Environ Med 60:237–243

    Article  CAS  PubMed  Google Scholar 

  • Huaux F, Louahed J, Hudspith B, Meredith C, Delos M, Renauld JC, Lison D (1998) Role of interleukin-10 in the lung response to silica in mice. Am J Respir Cell Mol Biol 18:51–59

    CAS  PubMed  Google Scholar 

  • Ichiba M, Nakajima K, Yamnak Y, Kiuchi N, Hirano T (1998) Autoregulation of the Stat3 gene through cooperation with a cAMP responsive element-binding protein. J Biol Chem 273:6132–6138

    Article  CAS  PubMed  Google Scholar 

  • Ihle JN (2001) The Stat family in cytokine signaling. Curr Opin Cell Biol 13:211–217

    Article  CAS  PubMed  Google Scholar 

  • Kehrer JP, Margolin SB (1997) Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice. Toxicol Lett 90:125–132

    Article  CAS  PubMed  Google Scholar 

  • Kishimoto T, Akira S, Narazaki M, Taga T (1995) Interleukin-6 family of cytokines and gp 130. Blood 86:1243–1254

    CAS  PubMed  Google Scholar 

  • Kubo M, Inoue H (2007) Suppressor of cytokine signalling 3 (Socs3) in Th2 cells evokes Th2 cytokines, IgE, and eosinophilia. Curr Allergy Asthma Rep 6:32–39

    Article  Google Scholar 

  • Legal Resource Centre (2009) Press release on the silicosis matter. [Available: http://www.Irc.org.za/pressrelease/1135]

  • Marini M, Vittori E, Hollemborg J, Mattoli S (1992) Expression of the potent inflammatory cytokines, granulocyte macrophage-colony stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma. J Allergy Clin Immunol 89:1001–1009

    Article  CAS  PubMed  Google Scholar 

  • McDonald JC, McDonald AD (1995) Chrysotile, tremolite, and mesothelioma. Science 267:776–777

    CAS  PubMed  Google Scholar 

  • Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173

    Article  CAS  PubMed  Google Scholar 

  • Mosmann TR, Sad S (1996) The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 17:138–146

    Article  CAS  PubMed  Google Scholar 

  • Nario RC, Hubbard AK (1996) Silica exposure increases expression of pulmonary intercellular adhesion molecule-1 (ICAM-1) in C57Bl/6 mice. J Toxicol Environ Health 49:599–617

    Article  CAS  PubMed  Google Scholar 

  • Nicholson SE, Wilson TA, Farley A, Starr R, Zhang J-G, Baca M, Alexander WS, Hilton DJ, Metcalf, Nicola NA (1999) Mutational analysis of the SOCS proteins suggests a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J 18:375–385

    Article  CAS  PubMed  Google Scholar 

  • Olszewski MA, Huffnagle GB, McDonald RA, Lindell DM, Moore BB, Cook DN, Toews GB (2000) The role of macrophage inflammatory protein-1 alpha/CCL3 in regulation of T-cell-mediated immunity to Cryptococcus neoformans infection. J Immunol 165:6429–6436

    CAS  PubMed  Google Scholar 

  • Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP (1998) The pathophysiologic role of interleukin-6 in human disease. Ann Intern Med 128:127–137

    CAS  PubMed  Google Scholar 

  • Park HH, Girdeler-Brown BV, Churchyard GJ, White NW, Ehrilch RI (2009) Incidence of tuberculosis and HIV and progression of silicosis and lung function impairment among former basotho gold miners. Am J Ind Med 52:901–908

    Article  PubMed  Google Scholar 

  • Paul BN, Mishra V, Chaudhury B, Awasthi A, Das AB, Saxena U, Saxena A, Chauhan L, Kumar P, Raisuddin S (2009) Status of Stat3 in ovalbumin-induced mouse model of asthma: Analysis of the role of Socs3 and IL-6. Int Arch Allergy Immunol 148:99–108

    Article  CAS  PubMed  Google Scholar 

  • Prockop DJ, Kivirikko KI (1967) Relationship of hydroxyproline excretion in urine to collagen metabolism: biochemistry and clinical applications. Ann Intern Med 66:1243–1266

    CAS  Google Scholar 

  • Qiu Z, Fujimura M, Kurashima K, Nakao S, Mukaidaz N (2004) Enhanced airway inflammation and decreased subepithelial fibrosis in interleukin 6-deficient mice following chronic exposure to aerosolized antigen. Clin Exp Allergy 34:1321–1328

    Article  CAS  PubMed  Google Scholar 

  • Ranganathan S, Linnane B, Nolan G, Gangell C, Hall G (2008) Early detection of lung disease in children with cystic fibrosis using lung function. Paed Resp Rev 9:60–67

    Article  Google Scholar 

  • Reiser KM, Last JA (1979) Silicosis and fibrogenesis: fact and artifact. Toxicology 13:51–72

    CAS  PubMed  Google Scholar 

  • Saito H, Asakura K, Ogasawara H, Watanabe M, Kataura A (1997) Topical antigen provocation increases the number of immunoreactive IL-4-, IL-5- and IL-6-positive cells in the nasal mucosa of patients with perennial allergic rhinitis. Int Arch Allergy Immunol 114:81–85

    Article  CAS  PubMed  Google Scholar 

  • Sallusto F, Mackay CR, Lanzavecchia A (1997) Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells. Science 277:2005–2007

    Article  CAS  PubMed  Google Scholar 

  • Seki Y-I, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, Komine O, Hamano S, Himeno K, Inagaki-Ohara K, Cacalano N, O’Garra A, Oshida T, Saito H, Johnston JA, Yoshimura A, Kubo M (2003) SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses. Nat Med 9:1047–1057

    Article  CAS  PubMed  Google Scholar 

  • Shi X, Mao Y, Daniel LN, Saffiotti U, Dalal NS, Vallyathan V (1994) Silica radical-induced DNA damage and lipid peroxidation. Environ Health Perspect 102(suppl.10):149–154

    Article  CAS  PubMed  Google Scholar 

  • Simeonova PP, Toriumi W, Kommineni C, Erkan M, Munson AE, Rom WN, Luster MI (1997) Molecular regulation of IL-6 activation by asbestos in lung epithelial cells: role of reactive oxygen species. J Immunol 159:3921–3928

    CAS  PubMed  Google Scholar 

  • Simpson A, Hankinson J, Borg-Bartolo S, Lowe L, John S, Woodcock A, Ollier W, Custovic A (2007) Haplotype tagging SNPs in the beta adrenergic receptor (ADRB2) gene are associated with pre and post-bronchodilator Lung function in preschool children. J Allergy Clin Immunol 119:S1954

    Article  Google Scholar 

  • Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR, Jenkins BJ, Gonda TJ, Alexander WS, Metcalf D, Nicola NA, DJl Hilton (1997) A family of cytokine inducible inhibitors of signalling. Nature 387:917–921

    Article  CAS  PubMed  Google Scholar 

  • teWaternaude JM, Ehrlich RI, Churchyard GJ, Pemba L, Dekker K, Vermeis M, White NW, Thompson ML (2006) Tuberculosis and silica exposure in South African gold miners. Occup Environ Med 63:187–192

    Article  CAS  PubMed  Google Scholar 

  • Uguccioni M, Mackay CR, Ochensberger B, Loetscher P, Rhis S, LaRosa GJ, Rao P, Ponath PD, Baggiolini M, Dahinden CA (1997) High expression of the chemokine receptor CCR3 in human blood basophils: role in activation by eotaxin, MCP-4, and other chemokines. J Clin Invest 100:1137–1143

    Article  CAS  PubMed  Google Scholar 

  • Warmald S, Hilton DJ (2003) Inhibitors of cytokine signal transduction. J Biol Chem 279:821–824

    Article  Google Scholar 

  • Williams AO, Saffiotti U (1995) Transforming growth factor beta1, ras and p53 in silica-induced fibrogenesis and carcinogenesis. Scand J Work Environ Health 21:30–34

    CAS  PubMed  Google Scholar 

  • Williams AO, Flanders KC, Saffiotti U (1993) Immunohistochemical localization of transforming growth factor-ß1 in rats with experimental silicosis, alveolar type II hyperplasia, and lung cancer. Am J Pathol 142:1831–1840

    CAS  PubMed  Google Scholar 

  • Yokoyama A, Kohno N, Fujino S, Hamada Y, Inoue S, Fujioka S, Ishida S, Hiwada K (1995) Circulating interleukin-6 in patients with bronchial asthma. Am J Respir Crit Care Med 151:1354–1358

    CAS  PubMed  Google Scholar 

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Acknowledgments

We thank K. C. Gupta, Director, Indian Institute of Toxicology Research, for encouragement, Piyali Dhar Chowdhury for critical discussion and revision of the manuscript and Dr. Sanghmitra Bandyopadhyay for stimulating discussion. This work is supported by Council of Scientific and Industrial Research (New Delhi) grant # NWP33. This is IITR communication # 2812.

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Authors and Affiliations

  1. Immunobiology Division, Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow, 226001, India

    Shambhoo Sharan Tripathi, Vani Mishra, Mamta Shukla, Mukesh Verma, Jasmeet Kaur Chhabra & Bholanath Paul

  2. Histopathology Division, Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow, 226001, India

    Bhushan Pradosh Chaudhury

  3. Animal Facility Centre, Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow, 226001, India

    Pradeep Kumar

  4. Department of Biochemistry, Banaras Hindu University, Varanasi, India

    Haushila Prasad Pandey

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  1. Shambhoo Sharan Tripathi
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Sharan Tripathi, S., Mishra, V., Shukla, M. et al. IL-6 receptor-mediated lung Th2 cytokine networking in silica-induced pulmonary fibrosis. Arch Toxicol 84, 947–955 (2010). https://doi.org/10.1007/s00204-010-0559-z

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