Abstract
The form of (1-3)-β-d glucan found in the cell walls of the anamorphic Trichocomaceae that grow on damp building materials is considered to have potent toxic and inflammatory effects on cells of the respiratory system. It is also considered to have a potential role in the development of non-allergenic respiratory health effects. While human studies involving experimental exposures all point to the inflammatory potential of pure curdlan, a linear (1-3)-β-d glucan in a triple helix configuration, animal experiments result in conflicting conclusions concerning the inflammatory potency of this glucan. However, because mice appear to be a better model than guinea pigs for exploring the respiratory effects of curdlan and because molecular mechanisms associated with this glucan remain largely unknown, we conducted further work to clarify the role of curdlan on the inflammatory response using our mouse model of lung disease. This study used in situ hybridization (ISH) to probe dectin-1 mRNA transcription with a digoxigenin-labeled cDNA probe, with reverse transcription (RT)-PCR based arrays used to measure inflammation gene and receptor transcriptional responses. Also, immunohistochemistry (IHC) was used to probe dectin-1 as well as anti-mouse Ccl3, Il1-alpha, and TNF-alpha expression to evaluate dose and time-course (4 and 12 h) postexposure (PE) response patterns in the lungs of intratracheally instilled mice exposed to a single 50 μl dose of curdlan at 10−7, 10−8, 10−9, and 10−10 M/animal (=4 μg to 4 ng curdlan/kg lung wt). Dectin-1 mRNA transcription and expression was observed in bronchiolar epithelium, alveolar macrophages (AMs), and alveolar type II cells (ATIIs) of lungs exposed to 4 μg to 40 ng curdlan/kg lung wt, at both time points. Compared to controls, array analysis revealed that 54 of 83 genes assayed were significantly modulated by curdlan. mRNA transcription patterns showed both dose and time dependency, with highest transcription levels in 10−7 and 10−8 M treatment animals, especially at 4-h PE. Nine gene mRNA transcripts (Ccl3, Ccl11, Ccl17, Ifng, Il1α, Il-20, TNF-α, Tnfrsf1b, and CD40lg) were significantly expressed at all doses suggesting they may have a central role in immunomodulating curdlan exposures. IHC revealed Ccl3, Il1-alpha, and TNF-alpha expression in bronchiolar epithelium, AMs and ATIIs illustrate the important immunomodulatory role that these cells have in the recognition of, and response to glucan. Collectively, these results confirm the inflammatory nature of curdlan and demonstrate the complex of inflammation-associated gene responses induced by (1-3)-β-d glucan in triple helical forms. These observations also provide a biological basis for the irritant and inflammatory response to curdlan observed in humans and animals in experimental studies.
Similar content being viewed by others
References
Allen MJ, Voelker DR, Mason RJ (2001) Interactions of surfactant proteins A and D with Saccharomyces cerevisiae and Aspergillus fumigatus. Infect Immun 69:2037–2044
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, Gordon S (2001) Immune recognition. A new receptor for beta-glucans. Nature 413:36–37
Brown JS, Wilson WE, Grant LD (2005) Dosimetric comparisons of particle deposition and retention in rats and humans. Inhal Toxicol 17:355–385
CCAC (1993) Guide to the care and use of experimental animals, vol 1. Bradda Printing Services, Ottawa
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
Didierlaurent A, Brissoni B, Velin D, Aebi N, Tardivel A, Käslin E, Sirard JC, Angelov G, Tschopp J, Burns K (2006) Tollip regulates pro-inflammatory responses to interleukin-1 and lipopolysaccharide. Mol Cell Biol 26:735–742
Doucette C, Giron-Michel J, Canonica GW, Azzarone B (2002) Human lung myofibroblasts as effectors of the inflammatory process: the common receptor λ chain is induced by Th2 cytokines, and CD40 ligand is induced by lipopolysaccharide, thrombin and TNF-α. Eur J Immunol 32:2437–2449
Douwes J (2005a) Health effects of 1, 3 β glucans: the epidemiological evidence. In: Young S–H, Castranova V (eds) Toxicology of (1–3)-beta-d-glucans. CRC Press, Boca Raton, pp 35–52
Douwes J (2005b) (1–3)-beta-d-glucans and respiratory health: a review of the scientific literature. Indoor Air 15:160–169
Elizur A, Adair-Kirk TL, Kelley DG, Griffin GL, de Mello DE, Senior RM (2008) Tumor necrosis factor -α from macrophages enhances LPS-induced Clara cell expression of keratinocyte-derived chemokine. Am J Respir Cell Mol Biol 38:8–15
Ferwerda G, Meyer-Wentrup F, Kullberg B-J, 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
Fogelmark B, Goto H, Yuasa K, Marchat B, Rylander R (1992) Acute pulmonary toxicity of inhaled beta-1,3-glucan and endotoxin. Agents Actions 35:50–56
Fogelmark B, Sjostrand M, Williams D, Rylander R (1997) Inhalation toxicity of (1, 3)-β-d-glucan: recent advances. Mediators Inflamm 6:263–265
Foto M, Plett J, Berghout J, Miller JD (2004) Modification of the Limulus Amebocyte Lysate assay for the analysis of glucan in indoor environments. Anal Bioanal Chem 379:156–162
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 15:257–266
Furuzawa M, Kuwahara M, Ishii K, Iwakura Y, Tsubone H (2002) Diurnal variation of heart rate, locomotor activity, and body temperature in interleukin-1α/β doubly deficient mice. Exp Anim 51:49–56
Gregory L, Pestka JJ, Dearborn D, Rand TG (2004) Localization of satratoxin-G in Stachybotrys chartarum spores and spore-impacted mouse lung tissues using immunocytochemistry. Toxicol Path 32:26–34
Happerfield LC, Echezarreta G, Gillett CG (1996) Assessment of oestrogen and progesterone receptor antibodies in formalin-fixed routinely processed paraffin-wax embedded tissue. J Clin Pathol 1:170–178
Health Canada (2004) Fungal contamination in public buildings: health effects and investigation methods. Health Canada, Ottawa, Ontario. ISBN 0-662-37432-0
Hernandez-Novoa B, Bishop L, Logun C, Munson PJ, Elnekave E, Rangel ZG, Barb J, Danner RL, Kovacs JA (2008) Immune responses to Pneumocystis murina are robust in healthy mice but largely absent in CD40 ligand- deficient mice. J Leukoc Biol 84:420–430
Holck P, Sletmoen M, Stokke BT, Permin H, Norn S (2007) Potentiation of histamine release by microfungal (1, 3)- and (1, 6)-β-d-glucans. Basic Clin Pharm Toxicol 101:455–458
Huaux F, Gharaee-Kermani M, Liu T, Morel V, McGarry B, Ullenbruch M, Kunkel SL, Wang J, Xing Z, Phan SH (2005) Role of Eotaxin-1 (CCL11) and CC chemokine receptor 3 (CCR3) in bleomycin-induced lung injury and fibrosis. Am J Pathol 167:1485–1496
Ishida Y, Kimura A, Kondo T, Hayashi T, Ueno M, Takakura N, Matsushima K, Mukaida N (2007) Essential roles of the CC chemokine ligand 3-CC chemokine receptor 5 axis in bleomycin-induced pulmonary fibrosis through regulation of macrophage and fibrocyte infiltration. Am J Pathol 170:843–854
Jeyaseelan S, Chu HW, Young SK, Worthen GS (2004) Transcriptional profiling of lipopolysaccharide-induced acute lung injury. Infect Immun 72:7247–7256
Jowett T (1997) Tissue in situ hybridization: methods in animal development. John Wiley, New York
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
Kaufman J, Sime PJ, Phipps RP (2004) Expression of CD154 (CD40 ligand) by human lung fibroblasts: differential regulation by IFN-λ and IL-13, and implications for fibrosis. J Immunol 172:1862–1871
Kelly MM, McNagny K, Williams DL, van Rooijen N, Maxwell L, Gwozd C, Mody CH, Kubes P (2008) The lung responds to zymosan in a unique manner independent of toll-like receptors, complement, and dectin-1. Am J Respir Cell Mol Biol 38:227–238
Kelsen SG, Aksoy MO, Yang Y, Shahabuddin S, Litvin J, Safadi F, Rogers TJ (2004) The chemokine receptor CXCR3 and its splice variant are expressed in human airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 287:584–591
Kleinstreuer C, Zhang Z, Kim CS (2007) Combined inertial and gravitational deposition of microparticles in small model airways of the human respiratory system. J Aerosol Sci 38:1047–1061
Kleinstreuer C, Zhang Z, Li Z (2008) Modeling airflow and particle transport/deposition in pulmonary airways. Resp Physiol Neurobiol 163:128–138
Lloyd C (2002) Chemokines in allergic lung disease. Immunology 105:144–154
Mason CD, Rand TG, Oulton M, MacDonald HM, Scott JE (1998) Effects of Stachybotrys chartarum (atra) conidia and isolated toxin on lung surfactant production and homeostasis. Nat Toxins 6:27–33
Mason C, Rand TG, Oulton M, MacDonald J (2001) The effect of Stachybotrys chartarum spores and an isolated trichothecene, isosatratoxin F, on convertase activity in mice. Toxicol Appl Pharmacol 172:21–28
Miller JD, Rand TG, Jarvis BB (2003) Stachybotrys chartarum: cause of human disease or media darling? Med Mycol 41:271–291
Murphy K, Travers P, Walport M (2008) Janeway’s immunobiology. Garland science. Taylor & Francis, New York
Murray HM, Gallant JW, Perez-Casanova JC, Johnson SC, Douglas SE (2003) Ontogeny of lipase expression in winter flounder. J Fish Biol 62:816–833
National Academy of Sciences (2004) Damp indoor air spaces and health. National Academies Press, Washington, DC
Ohkawara Y, Lei XF, Stampfli MR, Marshall JS, Xing Z, Jordana M (2005) Cytokine and eosinophil responses in the lung, peripheral blood, and bone marrow compartments in a murine model of allergen-induced airways inflammation. Am J Respir Crit Care Med 16:510–520
Ohno N, Miura T, Miura NN, Adachi Y, Yadomae T (2001) Structure and biological activities of hypochlorite oxidized zymosan. Carbohydr Polym 44:339–349
Palma AS, Feizi T, Zhang Y, Stoll MS, Lawson AM, Diaz-Rodriguez E, Campanero-Rhodes MA, Costa J, Gordon S, Brown GD, Chai W (2006) Ligands for the β-glucan receptor, dectin-1, assigned using “designer” microarrays of oligosaccharide probes (Neoglycolipids) generated from glucan polysaccharides. J Biol Chem 281:5771–5779
Pease JE, Sabroe I (2002) The role of interleukin-8 and its receptors in inflammatory lung disease: implications for therapy. Am J Respir Med 1:19–25
Phalen RF, Oldham MJ, Wolff RK (2008) The relevance of animal models for aerosol studies. J Aerosol Med Pulm Drug Deliv 21:113–124
Rand TG, Miller JD (2008) Immunohistochemical and immunocytochemical detection of Sch34 antigen in Stachybotrys chartarum spores and spore impacted mouse lungs. Mycopathologia 165:73–80
Rand TG, Giles S, Flemming J, Miller JD, Puniani E (2005) Inflammatory and cytotoxic responses in mouse lungs exposed to purified toxins from building isolated Penicillium brevicompactum Dierckx and P. chrysogenum Thom. Toxicol Sci 87:213–222
Rand TG, Flemming J, Miller JD, Womiloju T (2006) Inflammatory and cytotoxic responses in mouse lungs toward atranones A and C from Stachybotrys chartarum. J Toxicol Environ Health A 69:1239–1251
Reid DM, Montoya M, Taylor PR, Borrow P, Gordon S, Brown GD, Wong SYC (2004) Expression of the β-glucan receptor, dectin-1, on murine leukocytes in situ correlates with its function in pathogen recognition and reveals potential roles in leukocyte interactions. J Leukoc Biol 76:86–94
Reponen T, Seo S-C, Grimsley F, Lee T, Crawford C, Grinshpun SA (2007) Fungal fragments in mouldy houses: a field study in homes in New Orleans and southern Ohio. Atmos Environ 41:8140–8149
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
Rylander R, Lin RH (2000) (1, 3) beta-d-glucan—relationship to indoor air related symptoms, allergy and asthma. Toxicology 152:47–52
Rylander R, Persson K, Goto H, Yuasa K, Shigenori T (1992) Airborne bet-1-3 glucan may be related to symptoms in sick buildings. Indoor Environ 1:263–267
Salares VR, Hinde CA, Miller JD (2009) Analysis of settled dust in homes and fungal glucan in air particulate collected during HEPA vacuuming. Indoor Built Environ (in press)
Sambrook J, Fritch EF, Maniatis T (1989) Molecular cloning: a laboratory manual. Cold Spring laboratory Press, NY
Schuyler M, Gott K, Cherne A (1998) Effect of glucan on murine lungs. J Toxicol Environ Health A 53:493–505
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 Respir J 16:140–145
Sjostrand M, Rylander R (1997) Pulmonary cell infiltration after chronic exposure to (1, 3) beta-d-glucan and cigarette smoke. Inflamm Res 46:93–97
Sorenson WG, Shahan TA, Simpson J (1998) Cell wall preparations from environmental yeasts: effect on alveolar macrophage function in vitro. Ann Agric Environ Med 5:65–71
Steele C, Rapaka RR, Metz A, Pop SM, Williams DL, Gordon S, Kolls JK, Brown GD (2005) The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. Pathogens 1:323–334
Straszek SP, Adamcakova-Dodd A, Metwali N, Pedersen OF, Sigsgaard T, Thorne PS (2007) Acute effect of glucan-spiked office dust on nasal and pulmonary inflammation in guinea pigs. J Toxicol Environ Health A 70:1923–1928
Suzaki Y, Hamada K, Nomi T, Ito T, Sho M, Kai Y, Nakajima Y, Kimura H (2008) A small-molecule compound targeting CCR5 and CXCR3 prevents airway hyper-responsiveness and inflammation. Eur Respir J 31:783–789
Tanaka S, Aketagawa J, Takahashi S, Shibata Y (1991) Activation of limulus coagulation factor G by (1, 3) beta d glucans. Carbohydr Res 218:167–174
Taylor PR, Tsoni VS, Willment JA, Dennehy KM, Rosas M, Findon H, Haynes K, Steele C, Botto M, Gordon S, Brown GD (2006) Dectin-1 is required for glucan recognition and control of fungal infection. Nat Immunol 8:31–38
Torrelles JB, Azad AK, Henning LN, Carlson TK, Schlesinger LS (2008) Role of C-type lectins in mycobacterial infections. Curr Drug Targets 9:102–112
Vassallo R, Standing JE, Limper AH (2000) Isolated Pneumocystis carinii cell wall glucan provokes lower respiratory tract inflammatory responses. J Immunol 164:3755–3763
Willment JA, Gordon S, Brown G (2001) Characterization of the human beta-glucan receptor and its alternatively spliced isoforms. J Biol Chem 276:43818–43823
Yang Z, Marshall JS (2009) Zymosan treatment of mouse mast cells enhances dectin-1 expression and induces dectin-1-dependent reactive oxygen species (ROS) generation. Immunobiology 214:321–330
Young S–H, Robinson VA, Barger M, Porter DW, Frazer DG, Castranova V (2001) Acute inflammation and recovery in rats after intratracheal instillation of a 1,3-beta-glucan (zymosan A). J Toxicol Environ Health A 64:311–325
Young S–H, Robinson VA, Barger M, Frazer DG, Castranova V, Jacobs RR (2003a) Partially opened triple helix is the biologically active conformation of 1,3-beta-glucans that induces pulmonary inflammation in rats. J Toxicol Environ Health A 66:551–563
Young S–H, Robinson V, Barger M, Whitmer M, Porter D, Frazer D, Castranova V (2003b) Exposure to particulate 1,3 beta glucans induces greater pulmonary toxicity than soluble 1,3 beta glucans in rats. J Toxicol Environ Health A 66:25–38
Young S–H, Roberts JR, Antonini JM (2006) Pulmonary exposure to 1 → 3 -β-glucan alters adaptive immune responses in rats. Inhal Toxicol 18:865–874
Acknowledgments
We thank J. Gallant, C. Leggiadro, J. Monholland, and C. Murphy, NRC Institute of Marine Biosciences, Halifax, Nova Scotia for assistance and excellent technical support. Additionally, 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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rand, T.G., Sun, M., Gilyan, A. et al. Dectin-1 and inflammation-associated gene transcription and expression in mouse lungs by a toxic (1,3)-β-d glucan. Arch Toxicol 84, 205–220 (2010). https://doi.org/10.1007/s00204-009-0481-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-009-0481-4