The signal transducer and activator of transcription 6 (STAT-6) mediates Th2 inflammation and tissue damage in a murine model of peanut-induced food allergy
Main Article Content
Keywords
Gut inflammation, Food allergy, STAT-6
Abstract
Introduction: Food allergies are inflammatory conditions mediated by Th2 and probably STAT-6 dependent immune responses.
Objective and design: Here we investigated the role of Signal Transducer and Activator of Transcription 6 (STAT-6) in development of inflammation in peanut allergy.
Methods: To induce food allergy, wild-type (WT) and mice deficient for STAT-6 (Stat6−/−) were sensitized with peanut proteins and challenged with peanut seeds.
Results: WT animals lost weight and refused the peanut diet, in contrast to Stat6−/− mice, which had a better maintenance of body weight and more regular seeds’ consumption. The augmented peanut-specific IgG, IgG1 and IgE in the allergic WT was abolished in Stat6−/− animals that also presented increased IgG2a. There was an overall reduction in the gut mediators in the absence of STAT-6, including those related to inflammatory and Th2 responses, in contrast to a rising counter regulatory and Th1 reaction in Stat-6−/− mice. These animals had IFN- and IL-10 similar to WT after the four-week challenge. Most interestingly, Stat-6−/− mice had no intestinal damage, in contrast to WT animals, which had inflammatory infiltrate, tissue destruction, epithelial exulceration, edema, congestion and loss of villous architecture in the small gut segments.
Conclusions: STAT-6 plays an important role in the establishment of the Th2 inflammatory responses and intestinal damage in peanut allergy.
References
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10. van Panhuys N, Tang SC, Prout M, Camberis M, Scarlett D, Roberts J, et al. In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation. Proc Natl Acad Sci U S A. 2008;105:12423-8.
11. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4:313-9.
12. Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, et al. Essential role of Stat6 in IL-4 signalling. Nature. 1996;380:627---30.
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17. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997;89:587-96.
18. Zhu J, Cote-Sierra J, Guo L, Paul WE. Stat5 activation plays a critical role in Th2 differentiation. Immunity. 2003; 19:739-48.
19. Kweon MN, Yamamoto M, Kajiki M, Takahashi I, Kiyono H. Systemically derived large intestinal CD4(+) Th2 cells play a central role in STAT6-mediated allergic diarrhea. J Clin Investig. 2000;106:199-206.
20. Akimoto T, Numata F, Tamura M, Takata Y, Higashida N, Takashi T, et al. Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity in signal transducers and activators of transcription (STAT) 6-deficient mice. J Exp Med. 1998;187:1537-42.
21. Tekkanat KK, Maassab HF, Cho DS, Lai JJ, John A, Berlin A, et al. IL-13-induced airway hyperreactivity during respiratory syncytial virus infection is STAT6 dependent. J Immunol. 2001;166:3542-8.
22. Cardoso CR, Provinciatto PR, Godoi DF, Vieira TS, Ferreira BR, Teixeira G, et al. B cells are involved in the modulation of pathogenic gut immune response in food-allergic enteropathy. Clin Exp Immunol. 2008;154:153-61.
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25. Amoli MM, Hand S, Hajeer AH, Jones KP, Rolf S, Sting C, et al. Polymorphism in the STAT6 gene encodes risk for nut allergy. Genes Immun. 2002;3:220-4.
26. Hancock DB, Romieu I, Chiu GY, Sienra-Monge JJ, Li H, Estela Del Rio-Navarro B, et al. STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children. J Allergy Clin Immunol. 2012;129:1673-6.
27. van Ginkel CD, Pettersson ME, Dubois AEJ, Koppelman GH. Association of STAT6 gene variants with food allergy diagnosed by double-blind placebo-controlled food challenges. Allergy. 2018;73:1337-41.
28. Potaczek DP, Kabesch M. Current concepts of IgE regulation and impact of genetic determinants. Clin Exp Allergy. 2012;42:852---71.
29. Cardoso CR, Teixeira G, Provinciatto PR, Godoi DF, Ferreira BR, Milanezi CM, et al. Modulation of mucosal immunity in a murine model of food-induced intestinal inflammation. Clin Exp Allergy. 2008;38:338-49.
30. Krishnamurthy P, Kaplan MH. STAT6 and PARP family members in the development of T cell-dependent allergic inflammation. Immune Netw. 2016;16:201-10.
31. Mabelane T, Basera W, Botha M, Thomas HF, Ramjith J, Levin ME. Predictive values of alpha-gal IgE levels and alphagal IgE: total IgE ratio and oral food challenge proven meat allergy in a population with a high prevalence of reported red meat allergy. Pediatr Allergy Immunol. 2018;29(8):841-9, http://dx.doi.org/10.1111/pai.12969.
32. Abdel-Gadir A, Schneider L, Casini A, Charbonnier LM, Little SV, Harrington T, et al. Oral immunotherapy with omalizumab reverses the Th2 cell-like programme of regulatory T cells and restores their function. Clin Exp Allergy. 2018;48:825-36.
33. Kupczyk M, Kuna P. Benralizumab: an anti-IL-5 receptor alpha monoclonal antibody in the treatment of asthma. Immunotherapy. 2018;10:349-59.
34. Mishra A, Rothenberg ME. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6- dependent mechanism. Gastroenterology. 2003;125:1419-27.
35. Blanchard C, Durual S, Estienne M, Emami S, Vasseur S, Cuber JC. Eotaxin-3/CCL26 gene expression in intestinal epithelial cells is up-regulated by interleukin-4 and interleukin-13 via the signal transducer and activator of transcription 6. Int J Biochem Cell Biol. 2005;37:2559-73.
36. Weissler KA, Rasooly M, DiMaggio T, Bolan H, Cantave D, Martino D, et al. Identification and analysis of peanut-specific effector T and regulatory T cells in children allergic and tolerant to peanut. J Allergy Clin Immunol. 2018;141, 1699-710.e7.
37. Tordesillas L, Berin MC. Mechanisms of oral tolerance. Clin Rev Allergy Immunol. 2018;55(2):107-17, http://dx.doi.org/10.1007/s12016-018-8680-5.
38. Noval Rivas M, Burton OT, Wise P, Charbonnier LM, Georgiev P, Oettgen HC, et al. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity. 2015;42:512-23.
39. Burton OT, Darling AR, Zhou JS, Noval-Rivas M, Jones TG, Gurish MF, et al. Direct effects of IL-4 on mast cells drive their intestinal expansion and increase susceptibility to anaphylaxis in a murine model of food allergy. Mucosal Immunol. 2013;6:740-50.
40. Chen CY, Lee JB, Liu B, Ohta S, Wang PY, Kartashov AV, et al. Induction of interleukin-9-producing mucosal mast cells promotes susceptibility to IgE-mediated experimental food allergy. Immunity. 2015;43:788-802.
2. Metcalfe DD. Food allergy. Curr Opin Immunol. 1991;3:881-6.
3. Sicherer SH, Leung DY. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects. J Allergy Clin Immunol. 2005;116:153-63.
4. Fischer R, McGhee JR, Vu HL, Atkinson TP, Jackson RJ, Tome D, et al. Oral and nasal sensitization promote distinct immune responses and lung reactivity in a mouse model of peanut allergy. Am J Pathol. 2005;167:1621-30.
5. Pansare M, Kamat D. Peanut allergies in children - a review. Clin Pediatr (Phila). 2009;48:709-14.
6. Moneret-Vautrin DA, Rance F, Kanny G, Olsewski A, Gueant JL, Dutau G, et al. Food allergy to peanuts in France- evaluation of 142 observations. Clin Exp Allergy. 1998; 28:1113-9.
7. Sicherer SH, Furlong TJ, Munoz-Furlong A, Burks AW, Sampson HA. A voluntary registry for peanut and tree nut allergy: characteristics of the first 5149 registrants. J Allergy Clin Immunol. 2001;108:128-32.
8. Al-Muhsen S, Clarke AE, Kagan RS. Peanut allergy: an overview. CMAJ. 2003;168:1279-85.
9. Mohrs M, Shinkai K, Mohrs K, Locksley RM. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. Immunity. 2001;15:303-11.
10. van Panhuys N, Tang SC, Prout M, Camberis M, Scarlett D, Roberts J, et al. In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation. Proc Natl Acad Sci U S A. 2008;105:12423-8.
11. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4:313-9.
12. Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S, et al. Essential role of Stat6 in IL-4 signalling. Nature. 1996;380:627---30.
13. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT, Tripp RA, et al. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996;380:630-3.
14. Kotanides H, Reich NC. Requirement of tyrosine phosphorylation for rapid activation of a DNA binding factor by IL. Science. 1993;262:1265-7.
15. Quelle FW, Shimoda K, Thierfelder W, Fischer C, Kim A, Ruben SM, et al. Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol Cell Biol. 1995;15:3336-43.
16. Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL. An interleukin-4-induced transcription factor: IL-4 Stat. Science. 1994;265:1701-6.
17. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997;89:587-96.
18. Zhu J, Cote-Sierra J, Guo L, Paul WE. Stat5 activation plays a critical role in Th2 differentiation. Immunity. 2003; 19:739-48.
19. Kweon MN, Yamamoto M, Kajiki M, Takahashi I, Kiyono H. Systemically derived large intestinal CD4(+) Th2 cells play a central role in STAT6-mediated allergic diarrhea. J Clin Investig. 2000;106:199-206.
20. Akimoto T, Numata F, Tamura M, Takata Y, Higashida N, Takashi T, et al. Abrogation of bronchial eosinophilic inflammation and airway hyperreactivity in signal transducers and activators of transcription (STAT) 6-deficient mice. J Exp Med. 1998;187:1537-42.
21. Tekkanat KK, Maassab HF, Cho DS, Lai JJ, John A, Berlin A, et al. IL-13-induced airway hyperreactivity during respiratory syncytial virus infection is STAT6 dependent. J Immunol. 2001;166:3542-8.
22. Cardoso CR, Provinciatto PR, Godoi DF, Vieira TS, Ferreira BR, Teixeira G, et al. B cells are involved in the modulation of pathogenic gut immune response in food-allergic enteropathy. Clin Exp Immunol. 2008;154:153-61.
23. Cardoso CR, Provinciatto PR, Godoi DF, Ferreira BR, Teixeira G, Rossi MA, et al. IL-4 regulates susceptibility to intestinal inflammation in murine food allergy. Am J Physiol Gastrointest Liver Physiol. 2009;296:G593-600.
24. Tamura K, Suzuki M, Arakawa H, Tokuyama K, Morikawa A. Linkage and association studies of STAT6 gene polymorphisms and allergic diseases. Int Arch Allergy Immunol. 2003;131:33-8.
25. Amoli MM, Hand S, Hajeer AH, Jones KP, Rolf S, Sting C, et al. Polymorphism in the STAT6 gene encodes risk for nut allergy. Genes Immun. 2002;3:220-4.
26. Hancock DB, Romieu I, Chiu GY, Sienra-Monge JJ, Li H, Estela Del Rio-Navarro B, et al. STAT6 and LRP1 polymorphisms are associated with food allergen sensitization in Mexican children. J Allergy Clin Immunol. 2012;129:1673-6.
27. van Ginkel CD, Pettersson ME, Dubois AEJ, Koppelman GH. Association of STAT6 gene variants with food allergy diagnosed by double-blind placebo-controlled food challenges. Allergy. 2018;73:1337-41.
28. Potaczek DP, Kabesch M. Current concepts of IgE regulation and impact of genetic determinants. Clin Exp Allergy. 2012;42:852---71.
29. Cardoso CR, Teixeira G, Provinciatto PR, Godoi DF, Ferreira BR, Milanezi CM, et al. Modulation of mucosal immunity in a murine model of food-induced intestinal inflammation. Clin Exp Allergy. 2008;38:338-49.
30. Krishnamurthy P, Kaplan MH. STAT6 and PARP family members in the development of T cell-dependent allergic inflammation. Immune Netw. 2016;16:201-10.
31. Mabelane T, Basera W, Botha M, Thomas HF, Ramjith J, Levin ME. Predictive values of alpha-gal IgE levels and alphagal IgE: total IgE ratio and oral food challenge proven meat allergy in a population with a high prevalence of reported red meat allergy. Pediatr Allergy Immunol. 2018;29(8):841-9, http://dx.doi.org/10.1111/pai.12969.
32. Abdel-Gadir A, Schneider L, Casini A, Charbonnier LM, Little SV, Harrington T, et al. Oral immunotherapy with omalizumab reverses the Th2 cell-like programme of regulatory T cells and restores their function. Clin Exp Allergy. 2018;48:825-36.
33. Kupczyk M, Kuna P. Benralizumab: an anti-IL-5 receptor alpha monoclonal antibody in the treatment of asthma. Immunotherapy. 2018;10:349-59.
34. Mishra A, Rothenberg ME. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, eotaxin-1, and STAT6- dependent mechanism. Gastroenterology. 2003;125:1419-27.
35. Blanchard C, Durual S, Estienne M, Emami S, Vasseur S, Cuber JC. Eotaxin-3/CCL26 gene expression in intestinal epithelial cells is up-regulated by interleukin-4 and interleukin-13 via the signal transducer and activator of transcription 6. Int J Biochem Cell Biol. 2005;37:2559-73.
36. Weissler KA, Rasooly M, DiMaggio T, Bolan H, Cantave D, Martino D, et al. Identification and analysis of peanut-specific effector T and regulatory T cells in children allergic and tolerant to peanut. J Allergy Clin Immunol. 2018;141, 1699-710.e7.
37. Tordesillas L, Berin MC. Mechanisms of oral tolerance. Clin Rev Allergy Immunol. 2018;55(2):107-17, http://dx.doi.org/10.1007/s12016-018-8680-5.
38. Noval Rivas M, Burton OT, Wise P, Charbonnier LM, Georgiev P, Oettgen HC, et al. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity. 2015;42:512-23.
39. Burton OT, Darling AR, Zhou JS, Noval-Rivas M, Jones TG, Gurish MF, et al. Direct effects of IL-4 on mast cells drive their intestinal expansion and increase susceptibility to anaphylaxis in a murine model of food allergy. Mucosal Immunol. 2013;6:740-50.
40. Chen CY, Lee JB, Liu B, Ohta S, Wang PY, Kartashov AV, et al. Induction of interleukin-9-producing mucosal mast cells promotes susceptibility to IgE-mediated experimental food allergy. Immunity. 2015;43:788-802.
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Dec 15, 2019
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Cardoso, C., Provinciatto, P., Godoi, D., Fonseca, M., Ferreira, B., Teixeira, G., Cunha, F., Pinzan, C., & da Silva, J. (2019). The signal transducer and activator of transcription 6 (STAT-6) mediates Th2 inflammation and tissue damage in a murine model of peanut-induced food allergy. Allergologia Et Immunopathologia, 47(6), 535-543. https://all-imm.com/index.php/aei/article/view/269
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Cardoso, C., Provinciatto, P., Godoi, D., Fonseca, M., Ferreira, B., Teixeira, G., Cunha, F., Pinzan, C., & da Silva, J. (2019). The signal transducer and activator of transcription 6 (STAT-6) mediates Th2 inflammation and tissue damage in a murine model of peanut-induced food allergy. Allergologia Et Immunopathologia, 47(6), 535-543. https://all-imm.com/index.php/aei/article/view/269