Profile of Gene Expression in a Murine Model of Allergic Bronchopulmonary Aspergillosis
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感染与免疫杂志 2005年第7期
Allergy-Immunology Division, Medical College of Wisconsin, and Research Service, VA Medical Center, Milwaukee, Wisconsin
Neuromuscular Diseases Section, National Institutes of Health, Bethesda, Maryland
Capital Genomix, Inc., Rockville, Maryland
ABSTRACT
Allergic bronchopulmonary aspergillosis (ABPA) results from the interactions of the Aspergillus allergens and immune system of the patients. We studied the gene expression profile in a mouse model of ABPA. Of the 12,000 genes studied, 1,300 genes showed enhanced expression and represent chemokine, cytokine, growth factor, signal transduction, and transmembrane receptor genes as well as genes related to arginine metabolism.
TEXT
Allergic bronchopulmonary aspergillosis (ABPA) results from inhalation of Aspergillus fumigatus antigens and is characterized by a pronounced CD4+ Th2 lymphocyte response, which is evidenced by enhanced immunoglobulin E (IgE), eosinophils, and inflammatory responses (5). In recent years, there have been several attempts to delineate allergy-associated genes (9, 14, 15). As mice treated with A. fumigatus demonstrated features similar to those of human ABPA, we studied the profile of genes altered in the mouse model of ABPA (1, 3). The results indicate modulation of over 2,000 genes in mice, including enhanced expression of a number of Th2 cytokine genes.
Culture filtrate antigens from Aspergillus fumigatus were instilled into the nostrils of BALB/c mice with sterile micropipette tips as described before (6, 7). Serum IgE, A. fumigatus-specific IgG, and lung histology were studied as described before (6, 7).
RNA was isolated from the lungs of control and Aspergillus-exposed mice with TRIzol according to the recommended protocol of the manufacturer (Invitrogen Life Technologies, Carlsbad, CA). Fifteen micrograms total RNA was reverse transcribed (Invitrogen, Carlsbad, CA) and in vitro transcribed to obtain biotinylated cRNA using a transcript labeling kit (Enzo Diagnostics, Farmingdale, NY). After hybridization to the MG_U74Av2 GeneChip (Affymetrix, Santa Clara, CA), the chips were automatically washed and stained with streptavidin-phycoerythrins using a fluidics system. The signal was amplified with biotinylated antistreptavidin antibody, and the chips were scanned (Agilent Technologies, Palo Alto, CA). Gene transcript levels were determined from data image files using algorithms in the Micro Array Analysis Suite Software 5.0 and Data Mining Tools (Affymetrix; Santa Clara, CA). Fold differences in gene expression were calculated from the average normalized expression levels in the experimental and control groups.
Serum total IgE, A. fumigatus-specific IgG1, and eosinophils showed enhancement in the immunized mice compared to preimmunization sera and sera from control mice (data not shown). All the Aspergillus-immunized mice showed significant histological changes similar to ABPA, while all controls were normal (6). As reported previously in a series of communications, the antibody and eosinophil responses as well as histological and immunohistochemical findings in the A. fumigatus-exposed mice were comparable to responses in human ABPA (3, 6-8).
Of the total of about 12,000 genes studied, 2,471 genes demonstrated at least threefold changes after allergen administration (Table 1). There were genes that were upregulated or downregulated up to 25- or 28-fold, respectively, demonstrating a very active biological response on exposure to Aspergillus antigens. Among these, 1,362 genes were upregulated and 1,109 genes were downregulated. The genes that showed more-than-threefold changes were those involved in cytokine/chemokine expression, signal transduction pathways, and transmembrane receptor activities. On analysis of these genes using the gene ontology (GO) tools and DAVID, we identified 27 cytokine/chemokine-related genes, 130 genes related to signal transduction, and 87 genes with transmembrane receptor activity (Tables 1 and 2). The genes showing significant modulations are shown in Fig. 1, while genes representing arginine metabolism are shown in Table 3.
Twenty-seven genes belonging to cytokines, chemokines, and growth factors showed three- to eightfold increases in Aspergillus-challenged mice, and 9 showed suppression compared to controls (Table 2). Various extents of suppression were detected for tumor necrosis factor 1 alpha (TNF-1) receptor, CC chemokine ligands 4 and 12, transforming growth factor (TGF-), and gamma interferon (IFN-), while enhanced expression was shown by interleukin-5 (IL-5), IL-5 receptors, and CC chemokine receptors 4 and 5. The immunocytochemistry of the lung sections indicated a Th2 cytokine response, as evidenced by the presence of IL-4 and IL-5 but not IFN-.
Abnormal expression of 159 genes belonging to signal transduction and transmembrane receptors was demonstrable in antigen-exposed mice (Table 1). CD22, SDF receptor 2, CD44, Toll-like receptor 6 (TLR6), serotonin receptor, tyrosine kinase, prostaglandin receptors, and multiple histocompatibility molecule-related genes with direct immunological and allergic relevance showed increased expression (Table 1). Other significant genes showing enhanced expression are fibroblast growth factor 1, integrin, TNF, leukocyte tyrosine kinase, granulocyte-macrophage colony-stimulating factor, and platelet-derived growth factor receptor alpha.
Innate immunity is directly linked to certain receptors such as the TLRs. In Aspergillus-induced invasive disease, TLR2 plays a major role in imparting immunity. It is probable that the enhanced expression of TLR6 has a major role in the immunity of allergic aspergillosis. In the present study, we have demonstrated significant expression of several Th2-related genes such as the IL-4 and IL-5 receptor genes. In addition, there was also alteration in the expression of chemokine receptors such as CCR4 and CCR5 showing marked expression in A. fumigatus-exposed animals compared to control mice (11, 13). Another interesting observation is the augmentation of matrix metalloproteinase 9 in A. fumigatus-exposed mice. Previous studies indicate that this protein has a detrimental effect on the asthmatic responses by eliciting a Th2 type of response and in airway remodeling (12).
When genes involved in arginine metabolism were specifically analyzed, we found alteration of several of these genes (Table 3). Enhanced presence of arginase and NO has been reported in both human asthma and animal models of asthma (10, 17). Enzymes, arginase 1, ornithine transcarboxylase, and ornithine amino transferase are part of citric acid cycle of the respiratory metabolic pathway. Arginase catalyzes the conversion of L-arginine to urea and L-ornithine, depleting the availability of L-arginine substrate for inducible nitric oxide synthase (iNOS). It is believed that arginase competes with iNOS for their substrate L-arginine and inhibits NO production, as seen in experimental trypanosomiasis (2). It is also known that Th1 cytokines induce iNOS, whereas Th2 cytokines induce arginase. Arginase inhibits NO production and favors the synthesis of polyamines by producing L-ornithine, which is metabolized by ornithine decarboxylase to polyamines. The eightfold upregulation of S-adenosylmethionine decarboxylase (AMD1) is very pertinent as it catalyzes polyamine synthesis (Table 3), although its role in allergic diseases is not known (16).
Of the genes expressed in mice, none of the recently identified genes associated with asthma in humans, such as ADAM33, ESE-3, or PhFII, could be identified in the present study (4, 14, 15). This may be due to their restricted presence in humans or due to the lack of expression in the murine model, which is not known at present. The expression and suppression of the specific genes in the model of allergic aspergillosis may have significant implications as such information may provide better understanding of the disease mechanism as well as in developing therapeutic strategies.
ACKNOWLEDGMENTS
This investigation was supported by VA Medical Research.
The technical assistance of Laura Castillo and Nancy Elms and the editorial assistance of Donna Schrubbe are gratefully acknowledged.
REFERENCES
1. Blease, K., J. M. Schuh, C. Jakubzick, N. W. Lukacs, S. L. Kunkel, B. H. Joshi, R. K. Puri, M. H. Kaplan, and C. M. Hogaboam. 2002. Stat 6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma. Am. J. Pathol. 160:481-490.
2. Gobert, A. P., S. Daulouede, M. Lepoivre, J. L. Boucher, B. Bouteille, A. Buguet, R. Cespuglio, B. Veyret, and P. L. Vincendeau. 2000. L-Arginine availability modulates local nitric oxide production and parasitic killing in experimental trypanosomiasis. Infect. Immun. 68:4653-4657.
3. Grunig, G., and V. P. Kurup. 2003. Animal models of allergic bronchopulmonary aspergillosis. Front. Biosci. 8:e157-e171.
4. Howard, T. D., D. S. Postma, H. Jongepier, W. C. Moore, G. H. Koppelman, S. L. Zheng, J. Xu, E. R. Bleecker, and D. A. Meyers. 2003. Association of a disintegrin and metalloprotease 33 (ADAM 33) gene with asthma in ethnically diverse populations. J. Allergy Clin. Immunol. 112:717-722.
5. Kurup, V. P. 2004. Fungal allergy, p. 515-525. In D. K. Arora (ed.), Handbook of fungal biotechnology, 2nd ed. Marcel Dekker, New York, N.Y.
6. Kurup, V. P., S. Mauze, H. Y. Choi, B. W. P. Seymour, and R. L. Coffman. 1992. A murine model of allergic bronchopulmonary aspergillosis with elevated eosinophils and IgE. J. Immunol. 148:3783-3788.
7. Kurup, V. P., J. Q. Xia, R. Crameri, D. A. Rickaby, H. Y. Choi, S. Fluckiger, K. Blaser, C. A. Dawson, and K. J. Kelly. 2001. Purified recombinant A. fumigatus allergens induce different responses in mice. Clin. Immunol. 98:327-336.
8. Kurup, V. P., J. Q. Xia, H. Shen, D. A. Rickaby, J. D. Henderson, Jr., J. N. Fink, H. Chou, K. J. Kelly, and C. A. Dawson. 2002. Alkaline serine proteinase from Aspergillus fumigatus has synergistic effects on Asp-f-2-induced immune response in mice. Int. Arch. Allergy Immunol. 129:129-137.
9. Laitinen, T., A. Polvi, P. Rydman, J. Vendelin, V. Pulkkinen, P. Salmikangas, S. Makela, M. Rehn, A. Pirskanen, A. Rautanen, M. Zucchelli, H. Gullsten, M. Leino, H. Alenius, T. Petays, T. Haahtela, A. Laitinen, C. Laprise, T. J. Hudson, L. A. Laitinen, and J. Kere. 2004. Characterization of a common susceptibility locus for asthma-related traits. Science 304:300-304.
10. MacPherson, J. C., S. A. Comhair, S. C. Erzurum, D. F. Klein, M. F. Lipscomb, M. S. Kavuru, M. K. Samoszuk, and S. L. Hazen. 2001. Eosinophils are major source of nitric oxide-derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species. J. Immunol. 166:5763-5772.
11. Mantovani, A., P. A. Gray, J. Van Damme, and S. Sozzani. 2000. Macrophage derived chemokines (MDC). J. Leukoc. Biol. 68:400-404.
12. McMillan, S. J., J. Kearley, J. R. Campbell, X. W. Zhu, K. Y. Larbi, J. M. Shipley, R. M. Senior, S. Nourshargh, and C. M. Lloyd. 2004. Matrix metalloproteinase-9 deficiency results in enhanced allergen-induced airway inflammation. J. Immunol. 172:2586-2594.
13. Schuh, J. M., K. Blease, and C. M. Hogaboam. 2002. The role of CC chemokine receptor 5 (CCR5) and RANTES/CCL5 during chronic fungal asthma in mice. FASEB J. 16:228-230.
14. Silverman, E. S., R. M. Baron, L. J. Palmer, L. Le, A. Hallock, V. Subramaniam, R. J. Riese, M. D. McKenna, X. Gu, T. A. Libermann, A. Tugores, K. J. Haley, S. Shore, J. M. Drazen, and S. T. Weiss. 2002. Constitutive and cytokine-induced expression of the ETS transcription factor ESE-3 in the lung. Am. J. Respir. Cell Mol. Biol. 27:697-704.
15. Van Eerdewegh, P., R. D. Little, J. Dupuis, R. G. Del Mastro, K. Falls, J. Simon, D. Torrey, S. Pandit, J. McKenny, K. Braunschweiger, A. Walsh, Z. Liu, B. Hayward, C. Folz, S. P. Manning, A. Bawa, L. Saracino, M. Thackston, Y. Benchekroun, N. Capparell, M. Wang, R. Adair, Y. Feng, J. Dubois, M. G. FitzGerald, H. Huang, R. Gibson, K. M. Allen, A. Pedan, M. R. Danzig, S. P. Umland, R. W. Egan, F. M. Cuss, S. Rorke, J. B. Clough, J. W. Holloway, S. T. Holgate, and T. P. Keith. 2002. Association of the ADAM 33 gene with asthma and bronchial hyperresponsiveness. Nature 418:426-430.
16. Wang, W. W., C. P. Jenkinson, J. M. Griscavage, R. M. Kern, N. S. Arabolos, R. E. Byrns, S. D. Cederbaum, and L. J. Ignarro. 1995. Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide. Biochem. Biophys. Res. Commun. 210:1009-1016.
17. Zimmermann, N., N. E. King, J. Laporte, M. Yang, A. Mishra, S. M. Pope, E. E. Muntel, D. P. Witte, A. A. Pegg, P. S. Foster, Q. Hanid, and M. E. Rothenberg. 2003. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J. Clin. Investig. 111:1863-1874.(Viswanath P. Kurup, Ragha)
Neuromuscular Diseases Section, National Institutes of Health, Bethesda, Maryland
Capital Genomix, Inc., Rockville, Maryland
ABSTRACT
Allergic bronchopulmonary aspergillosis (ABPA) results from the interactions of the Aspergillus allergens and immune system of the patients. We studied the gene expression profile in a mouse model of ABPA. Of the 12,000 genes studied, 1,300 genes showed enhanced expression and represent chemokine, cytokine, growth factor, signal transduction, and transmembrane receptor genes as well as genes related to arginine metabolism.
TEXT
Allergic bronchopulmonary aspergillosis (ABPA) results from inhalation of Aspergillus fumigatus antigens and is characterized by a pronounced CD4+ Th2 lymphocyte response, which is evidenced by enhanced immunoglobulin E (IgE), eosinophils, and inflammatory responses (5). In recent years, there have been several attempts to delineate allergy-associated genes (9, 14, 15). As mice treated with A. fumigatus demonstrated features similar to those of human ABPA, we studied the profile of genes altered in the mouse model of ABPA (1, 3). The results indicate modulation of over 2,000 genes in mice, including enhanced expression of a number of Th2 cytokine genes.
Culture filtrate antigens from Aspergillus fumigatus were instilled into the nostrils of BALB/c mice with sterile micropipette tips as described before (6, 7). Serum IgE, A. fumigatus-specific IgG, and lung histology were studied as described before (6, 7).
RNA was isolated from the lungs of control and Aspergillus-exposed mice with TRIzol according to the recommended protocol of the manufacturer (Invitrogen Life Technologies, Carlsbad, CA). Fifteen micrograms total RNA was reverse transcribed (Invitrogen, Carlsbad, CA) and in vitro transcribed to obtain biotinylated cRNA using a transcript labeling kit (Enzo Diagnostics, Farmingdale, NY). After hybridization to the MG_U74Av2 GeneChip (Affymetrix, Santa Clara, CA), the chips were automatically washed and stained with streptavidin-phycoerythrins using a fluidics system. The signal was amplified with biotinylated antistreptavidin antibody, and the chips were scanned (Agilent Technologies, Palo Alto, CA). Gene transcript levels were determined from data image files using algorithms in the Micro Array Analysis Suite Software 5.0 and Data Mining Tools (Affymetrix; Santa Clara, CA). Fold differences in gene expression were calculated from the average normalized expression levels in the experimental and control groups.
Serum total IgE, A. fumigatus-specific IgG1, and eosinophils showed enhancement in the immunized mice compared to preimmunization sera and sera from control mice (data not shown). All the Aspergillus-immunized mice showed significant histological changes similar to ABPA, while all controls were normal (6). As reported previously in a series of communications, the antibody and eosinophil responses as well as histological and immunohistochemical findings in the A. fumigatus-exposed mice were comparable to responses in human ABPA (3, 6-8).
Of the total of about 12,000 genes studied, 2,471 genes demonstrated at least threefold changes after allergen administration (Table 1). There were genes that were upregulated or downregulated up to 25- or 28-fold, respectively, demonstrating a very active biological response on exposure to Aspergillus antigens. Among these, 1,362 genes were upregulated and 1,109 genes were downregulated. The genes that showed more-than-threefold changes were those involved in cytokine/chemokine expression, signal transduction pathways, and transmembrane receptor activities. On analysis of these genes using the gene ontology (GO) tools and DAVID, we identified 27 cytokine/chemokine-related genes, 130 genes related to signal transduction, and 87 genes with transmembrane receptor activity (Tables 1 and 2). The genes showing significant modulations are shown in Fig. 1, while genes representing arginine metabolism are shown in Table 3.
Twenty-seven genes belonging to cytokines, chemokines, and growth factors showed three- to eightfold increases in Aspergillus-challenged mice, and 9 showed suppression compared to controls (Table 2). Various extents of suppression were detected for tumor necrosis factor 1 alpha (TNF-1) receptor, CC chemokine ligands 4 and 12, transforming growth factor (TGF-), and gamma interferon (IFN-), while enhanced expression was shown by interleukin-5 (IL-5), IL-5 receptors, and CC chemokine receptors 4 and 5. The immunocytochemistry of the lung sections indicated a Th2 cytokine response, as evidenced by the presence of IL-4 and IL-5 but not IFN-.
Abnormal expression of 159 genes belonging to signal transduction and transmembrane receptors was demonstrable in antigen-exposed mice (Table 1). CD22, SDF receptor 2, CD44, Toll-like receptor 6 (TLR6), serotonin receptor, tyrosine kinase, prostaglandin receptors, and multiple histocompatibility molecule-related genes with direct immunological and allergic relevance showed increased expression (Table 1). Other significant genes showing enhanced expression are fibroblast growth factor 1, integrin, TNF, leukocyte tyrosine kinase, granulocyte-macrophage colony-stimulating factor, and platelet-derived growth factor receptor alpha.
Innate immunity is directly linked to certain receptors such as the TLRs. In Aspergillus-induced invasive disease, TLR2 plays a major role in imparting immunity. It is probable that the enhanced expression of TLR6 has a major role in the immunity of allergic aspergillosis. In the present study, we have demonstrated significant expression of several Th2-related genes such as the IL-4 and IL-5 receptor genes. In addition, there was also alteration in the expression of chemokine receptors such as CCR4 and CCR5 showing marked expression in A. fumigatus-exposed animals compared to control mice (11, 13). Another interesting observation is the augmentation of matrix metalloproteinase 9 in A. fumigatus-exposed mice. Previous studies indicate that this protein has a detrimental effect on the asthmatic responses by eliciting a Th2 type of response and in airway remodeling (12).
When genes involved in arginine metabolism were specifically analyzed, we found alteration of several of these genes (Table 3). Enhanced presence of arginase and NO has been reported in both human asthma and animal models of asthma (10, 17). Enzymes, arginase 1, ornithine transcarboxylase, and ornithine amino transferase are part of citric acid cycle of the respiratory metabolic pathway. Arginase catalyzes the conversion of L-arginine to urea and L-ornithine, depleting the availability of L-arginine substrate for inducible nitric oxide synthase (iNOS). It is believed that arginase competes with iNOS for their substrate L-arginine and inhibits NO production, as seen in experimental trypanosomiasis (2). It is also known that Th1 cytokines induce iNOS, whereas Th2 cytokines induce arginase. Arginase inhibits NO production and favors the synthesis of polyamines by producing L-ornithine, which is metabolized by ornithine decarboxylase to polyamines. The eightfold upregulation of S-adenosylmethionine decarboxylase (AMD1) is very pertinent as it catalyzes polyamine synthesis (Table 3), although its role in allergic diseases is not known (16).
Of the genes expressed in mice, none of the recently identified genes associated with asthma in humans, such as ADAM33, ESE-3, or PhFII, could be identified in the present study (4, 14, 15). This may be due to their restricted presence in humans or due to the lack of expression in the murine model, which is not known at present. The expression and suppression of the specific genes in the model of allergic aspergillosis may have significant implications as such information may provide better understanding of the disease mechanism as well as in developing therapeutic strategies.
ACKNOWLEDGMENTS
This investigation was supported by VA Medical Research.
The technical assistance of Laura Castillo and Nancy Elms and the editorial assistance of Donna Schrubbe are gratefully acknowledged.
REFERENCES
1. Blease, K., J. M. Schuh, C. Jakubzick, N. W. Lukacs, S. L. Kunkel, B. H. Joshi, R. K. Puri, M. H. Kaplan, and C. M. Hogaboam. 2002. Stat 6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma. Am. J. Pathol. 160:481-490.
2. Gobert, A. P., S. Daulouede, M. Lepoivre, J. L. Boucher, B. Bouteille, A. Buguet, R. Cespuglio, B. Veyret, and P. L. Vincendeau. 2000. L-Arginine availability modulates local nitric oxide production and parasitic killing in experimental trypanosomiasis. Infect. Immun. 68:4653-4657.
3. Grunig, G., and V. P. Kurup. 2003. Animal models of allergic bronchopulmonary aspergillosis. Front. Biosci. 8:e157-e171.
4. Howard, T. D., D. S. Postma, H. Jongepier, W. C. Moore, G. H. Koppelman, S. L. Zheng, J. Xu, E. R. Bleecker, and D. A. Meyers. 2003. Association of a disintegrin and metalloprotease 33 (ADAM 33) gene with asthma in ethnically diverse populations. J. Allergy Clin. Immunol. 112:717-722.
5. Kurup, V. P. 2004. Fungal allergy, p. 515-525. In D. K. Arora (ed.), Handbook of fungal biotechnology, 2nd ed. Marcel Dekker, New York, N.Y.
6. Kurup, V. P., S. Mauze, H. Y. Choi, B. W. P. Seymour, and R. L. Coffman. 1992. A murine model of allergic bronchopulmonary aspergillosis with elevated eosinophils and IgE. J. Immunol. 148:3783-3788.
7. Kurup, V. P., J. Q. Xia, R. Crameri, D. A. Rickaby, H. Y. Choi, S. Fluckiger, K. Blaser, C. A. Dawson, and K. J. Kelly. 2001. Purified recombinant A. fumigatus allergens induce different responses in mice. Clin. Immunol. 98:327-336.
8. Kurup, V. P., J. Q. Xia, H. Shen, D. A. Rickaby, J. D. Henderson, Jr., J. N. Fink, H. Chou, K. J. Kelly, and C. A. Dawson. 2002. Alkaline serine proteinase from Aspergillus fumigatus has synergistic effects on Asp-f-2-induced immune response in mice. Int. Arch. Allergy Immunol. 129:129-137.
9. Laitinen, T., A. Polvi, P. Rydman, J. Vendelin, V. Pulkkinen, P. Salmikangas, S. Makela, M. Rehn, A. Pirskanen, A. Rautanen, M. Zucchelli, H. Gullsten, M. Leino, H. Alenius, T. Petays, T. Haahtela, A. Laitinen, C. Laprise, T. J. Hudson, L. A. Laitinen, and J. Kere. 2004. Characterization of a common susceptibility locus for asthma-related traits. Science 304:300-304.
10. MacPherson, J. C., S. A. Comhair, S. C. Erzurum, D. F. Klein, M. F. Lipscomb, M. S. Kavuru, M. K. Samoszuk, and S. L. Hazen. 2001. Eosinophils are major source of nitric oxide-derived oxidants in severe asthma: characterization of pathways available to eosinophils for generating reactive nitrogen species. J. Immunol. 166:5763-5772.
11. Mantovani, A., P. A. Gray, J. Van Damme, and S. Sozzani. 2000. Macrophage derived chemokines (MDC). J. Leukoc. Biol. 68:400-404.
12. McMillan, S. J., J. Kearley, J. R. Campbell, X. W. Zhu, K. Y. Larbi, J. M. Shipley, R. M. Senior, S. Nourshargh, and C. M. Lloyd. 2004. Matrix metalloproteinase-9 deficiency results in enhanced allergen-induced airway inflammation. J. Immunol. 172:2586-2594.
13. Schuh, J. M., K. Blease, and C. M. Hogaboam. 2002. The role of CC chemokine receptor 5 (CCR5) and RANTES/CCL5 during chronic fungal asthma in mice. FASEB J. 16:228-230.
14. Silverman, E. S., R. M. Baron, L. J. Palmer, L. Le, A. Hallock, V. Subramaniam, R. J. Riese, M. D. McKenna, X. Gu, T. A. Libermann, A. Tugores, K. J. Haley, S. Shore, J. M. Drazen, and S. T. Weiss. 2002. Constitutive and cytokine-induced expression of the ETS transcription factor ESE-3 in the lung. Am. J. Respir. Cell Mol. Biol. 27:697-704.
15. Van Eerdewegh, P., R. D. Little, J. Dupuis, R. G. Del Mastro, K. Falls, J. Simon, D. Torrey, S. Pandit, J. McKenny, K. Braunschweiger, A. Walsh, Z. Liu, B. Hayward, C. Folz, S. P. Manning, A. Bawa, L. Saracino, M. Thackston, Y. Benchekroun, N. Capparell, M. Wang, R. Adair, Y. Feng, J. Dubois, M. G. FitzGerald, H. Huang, R. Gibson, K. M. Allen, A. Pedan, M. R. Danzig, S. P. Umland, R. W. Egan, F. M. Cuss, S. Rorke, J. B. Clough, J. W. Holloway, S. T. Holgate, and T. P. Keith. 2002. Association of the ADAM 33 gene with asthma and bronchial hyperresponsiveness. Nature 418:426-430.
16. Wang, W. W., C. P. Jenkinson, J. M. Griscavage, R. M. Kern, N. S. Arabolos, R. E. Byrns, S. D. Cederbaum, and L. J. Ignarro. 1995. Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide. Biochem. Biophys. Res. Commun. 210:1009-1016.
17. Zimmermann, N., N. E. King, J. Laporte, M. Yang, A. Mishra, S. M. Pope, E. E. Muntel, D. P. Witte, A. A. Pegg, P. S. Foster, Q. Hanid, and M. E. Rothenberg. 2003. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J. Clin. Investig. 111:1863-1874.(Viswanath P. Kurup, Ragha)