Abstract
People living in damp buildings are typically exposed to spore and mycelial fragments of the fungi that grow on damp building materials. There is experimental evidence that this exposure to triple-helical (1, 3)-β-d glucan and low molecular weight toxins may be associated with non-atopic asthma observed in damp and moldy buildings. However, the mechanisms underlying this response are only partially resolved. Using the pure (1, 3)-β-d glucan, curdlan, and the murine macrophage cell line, RAW 264.7, there were two objectives of this study. The first was to determine whether signal transduction pathways activating asthma-associated cell signaling pathways were stimulated using mouse transduction Pathway Finder® arrays and quantitative real-time (QRT) PCR. The second objective was to evaluate the dose and temporal responses associated with transcriptional changes in asthma-associated cytokines, the signal transduction receptor gene Dectin-1, and various transcription factor genes related to the induction of asthma using customized RT-PCR-based arrays. Compared to controls, the 10−7 M curdlan treatment induced significant changes in gene transcription predominately in the NFkB, TGF-β, p53, JAK/STAT, P13/AKT, phospholipase C, and stress signaling pathways. The 10−8 M curdlan treatment mainly induced NFkB and TGF-β pathways. Compared to controls, curdlan exposures also induced significant dose- and time-dependent changes in the gene translations. We found that that curdlan as a non-allergenic potentiator modulates a network of transduction signaling pathways not only associated with TH-1, TH-2, and TH-3 cell responses including asthma potentiation, but a variety of other cell responses in RAW 264.7 cells. These results help provide mechanistic basis for some of the phenotypic changes associated with asthma that have been observed in in vitro, in vivo, and human studies and open up a hypothesis-building process that could explain the rise of non-atopic asthma associated with fungi.
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References
Barnes P (2009) The cytokine network in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 41:631–638
Bauer S, Hartmann G, Goodridge H-S, Underhill DM (2008) Fungal recognition by TLR2 and Dectin-1. In: Hofmann F (ed) Toll-like receptors (TLRs) and innate immunity. Springer, Berlin Heidelberg, pp 87–109
Bonlokke JH, Stridh G, Sigsgaard T, Kjaergaard SK, Lofsted H, Andersson K, Bonefeld-Jorgensen EC, Jayatissa MN, Bodin L, Juto J-E, Molhave L (2006) Upper-airway inflammation in relation to dust spiked with aldehydes or glucan. Scand J Work Environ Health 32:374–382
Brown GD (2006) Dectin-1: a signaling non-TLR pattern-recognition receptor. Nature Rev Immunol 6:33–43
Chan G, Chan W, Sze D (2009) The effects of β-glucan on human immune and cancer cells. J Hematol Oncol 2:25–36
Cherid H, Foto M, Miller JD (2011) Performance of two different Limulus Amebocyte Lysate assays for the quantitation of fungal glucan. J Occ Environ Hygiene 8:540–543
Cox-Ganser JM, White SK, Jones R, Hilsbos K, Storey E, Enright PL, Rao CY, Kreiss K (2005) Respiratory morbidity in office workers in a water-damaged building. Environ Health Perspect 113:485–490
Crawford J (2010) Inflammation and Cancer: two pieces of the same puzzle. Cancer Prev Res 3:494–504
Czop JK (1986) The role of beta-glucan receptors on blood and tissue leukocytes in phagocytosis and metabolic activation. Pathol Immunopathol Res 5:286–296
Darnell JE (1997) STATs and gene regulation. Science 277:1630–1635
Drummond RA, Saijo S, Iwakura Y, Brown GD (2011) The role of Syk/CARD9 coupled C-type lectins in antifungal immunity. Eur J Immunol 41:276–281
Faro-Trindade I, Willment JA, Kerrigan AM, Redelinghuys P, Hadebe S, Reid DM, Srinivasan N, Wainwright H, Lang DM, Steele C, Brown GD (2012) Characterisation of innate fungal recognition in the lung. PLoS One 7:1–12
Ferwerda G, Meyer-Wentrup F, Kullberg BJ, Netea MG, Adema GJ (2008) Dectin-1 synergizes with TLR2 and TLR4 for cytokine production in human primary monocytes and macrophages. Cell Microbiol 10:2058–2066
Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A (2006) IL-13 signaling through the IL-13-alpha-2 receptor is involved in induction of TGF-beta-1 production and fibrosis. Nature Med 12:99–106
Foto M, Vrijmoed LLP, Miller JD, Ruest K, Lawton M, Dales RE (2005) Comparison of airborne ergosterol, glucan and Air-O-Cell data in relation to physical assessments of mold damage and some other parameters. Indoor Air 15:256–266
Grünebach F, Weck MM, Reichert J, Brossart P (2002) Molecular and functional characterization of human Dectin-1. Exp Hematol 30:1309–1315
Hudson B, Flemming J, Sun G, Rand TG (2005) Comparison of immunomodulator mRNA expression and concentration in lungs of Stachybotrys chartarum spore exposed mice. J Toxicol Environ Health A 68:1321–1335
Kasaian MT, Miller DK (2008) IL-13 as a therapeutic target for respiratory disease. Biochem Pharmacol 76:147–155
Kataoka K, Muta T, Yamazaki S, Takeshige K (2002) Activation of macrophages by Linear (1 → 3)-β -D-Glucans. Implications for the recognition of fungi by innate immunity. J Biol Chem 277:36825–36831
Kingeter LM, Lin X (2012) C-type lectin receptor-induced NF-κB activation in innate immune and inflammatory responses. Cell Mol Immunol 9:105–112
Martin KR (2012) Editorial: β-glucans: going through GM-CSF to get to dectin. J Leukoc Biol 91:521–524
Masuda Y, Togo T, Mizuno S, Konishi M, Nanba H (2012) Soluble β-glucan from Grifola frondosa induces proliferation and Dectin-1/Syk signaling in resident macrophages via the GM-CSF autocrine pathway. J Leukoc Biol 91:547–556
Mendell MJ, Mirer AG, Cheung K, Tong M, Douwes J (2011) Respiratory and allergic health effects of dampness, mold and dampness-related agents: a review of the epidemiologic evidence. Environ Health Perspect 119:748–756
Miller JD, Rand TG, McGregor H, Solomon J, Yang C (2008) Mold ecology: recovery of Fungi from certain moldy building materials. In: Prezant B, Weekes D, Miller JD (eds) Recognition Evaluation and Control of Indoor Mold. American Industrial Hygiene Association, Fairfax, pp 43–51
Miller JD, Sun M, Gilyan A, Roy J, Rand TG (2010) Inflammation-associated gene transcription and expression in mouse lungs induced by low molecular weight compounds from fungi from the built environment. Chemico-Biol Int 183:113–124
Mukherjee S, Chen L-Y, Papadimos TJ, Huang S, Zuraw BL, Pan ZK (2009) Lipopolysaccharide-driven Th2 cytokine production in macrophages is regulated by both MyD88 and TRAM. J Biol Chem 284:29391–29398
Neveu WA, Bernardo E, Allard JL, Nagaleekar V, Wargo MJ, Davis RJ, Iwakura Y, Whittaker LA, Rincon M (2011) Fungal allergen β-glucans trigger p38 mitogen-activated protein kinase-mediated IL-6 translation in lung epithelial cells. Am J Respir Cell Mol Biol 45:1133–1141
NIOSH (2012) Preventing occupational respiratory disease from exposures caused by dampness in office buildings, schools, and other nonindustrial buildings. National Institute for Occupational Safety and Health, Cincinnati, Ohio. DHHS (NIOSH) Publication No. 2013–102
Pernis AB, Rothman PB (2002) JAK-STAT signaling in asthma. J Clin Invest 109:1279–1283
Porter CM, Clipstone NA (2002) Sustained NFAT signaling promotes a Th1-Like pattern of gene expression in primary murine CD4+ T cells. J Immunol 168:4936–4945
Rand TG, Miller JD (2010) Toxins and inflammatory compounds. In: Flannigan B, Samson RA, Miller JD (eds) Microorganisms in home and indoor work environments Diversity, Health Impacts, Investigation and Control, second edition. CRC Press, Boca Raton, FL p. 291–206
Rand TG, Miller JD (2011) Toxicology and immunohistochemistry that shed light on health effects of fungi. ISIAQ, Austin
Rand TG, Sun M, Downey J, Gilyan A, Miller JD (2010) Inflammation- associated gene transcription and expression in mouse lungs by the (1, 3)-β-D glucan, curdlan. Arch Tox 84:205–220
Rand TG, DiPenta J, Robbins C, Miller JD (2011) Inflammation-associated gene modulation in mouse alveolar macrophages induced by low molecular weight compounds from fungi associated with damp building environments. Chemico-Biologic Int 190:139–147
Roy RM, Wüthrich M, Klein BS (2012) Chitin Elicits CCL2 from Airway Epithelial Cells and Induces CCR2-Dependent Innate Allergic Inflammation in the Lung. J Immunol 189:2545–2552
Rylander R (1993) Experimental exposures to 1, 3 beta D glucan. ASHRAE Trans 1993:338–340
Rylander R (1996) Airway responsiveness and chest symptoms after inhalations of endotoxin or (1, 3) beta D glucan. Indoor Built Environ 5:106–111
Shah VB, Ozment-Skelton TR, Williams DL, Keshvara L (2009) Vav1 and PI3 K are required for phagocytosis of beta-glucan and subsequent superoxide generation by microglia. Mol Immunol 46:1845–1853
Sigsgaard T, Bonefeld-Jorgensen EC, Kjaergaard SK, Mamas S, Pedersen OF (2000) Cytokine release from the nasal mucosa and whole blood after experimental exposures to organic dusts. Eur Resp J 16:140–145
Tak PP, Firestein GS (2001) NF-κB: a key role in inflammatory diseases. J Clin Invest 107:7–11
Tanaka S, Aketagawa J, Takahashi S (1991) Activation of Limulus coagulation factor G by (1,3)-β-D-glucans. Carbohydr Res 75:231–242
Van Dyken SJ, Garcia D, Porter P, Huang X, Quinlan PJ, Blanc PD, Corry DB, Locksley RM (2011) Fungal chitin from asthma-associated home environments induces eosinophilic lung infiltration. J Immunol 187:2261–2267
Vega K, Kalkum M (2012) Chitin, chitinase responses, and invasive fungal infections. Int J Microbiology: vol. 2012, Article ID 920459, 10 pages, 2012. doi:10.1155/2012/920459
Weiss ST (2010) What genes tell us about the pathogenesis of asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 181:1170–1173
WHO (2009) Guidelines for indoor air quality: dampness and mould. WHO Regional Office for Europe, DK-2100 Copenhagen 0, Denmark ISBN 978 92 890 4168 3
Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD (1998) Interleukin-13: central mediator of allergic asthma. Science 282:2258–2261
Wu AC, Lasky-Su J, Rogers CA, Klanderman BJ, Litonjua AA (2010) Fungal exposure modulates the effect of polymorphisms of chitinases on emergency department visits and hospitalizations. Am J Respir Crit Care Med 182:884–889
Xu S, Huo J, Lee KG, Kurosaki T, Lam KP (2009) Phospholipase C gamma 2 is critical for Dectin-1-mediated Ca2 + flux and cytokine production in dendritic cells. J Biol Chem 284:7038–7046
Young S-H, Roberts JR, Antonini JM (2006) Pulmonary exposure to 1, 3 -beta-glucan alters adaptive immune responses in rats. Inhal Toxicol 18:865–874
Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA (1999) Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 103:779–788
Acknowledgments
We thank Dr. G. Sun for use of the RT-PCR instrument. This work was supported by NSERC operating grants to T.G.R. and an NSERC IRC to J.D.M.
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Rand, T.G., Robbins, C., Rajaraman, D. et al. Induction of Dectin-1 and asthma-associated signal transduction pathways in RAW 264.7 cells by a triple-helical (1, 3)-β-d glucan, curdlan. Arch Toxicol 87, 1841–1850 (2013). https://doi.org/10.1007/s00204-013-1042-4
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DOI: https://doi.org/10.1007/s00204-013-1042-4