Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Role of Protease Activated Receptor 2 (PAR2) in Aspergillus Protease Allergen Induces Th2 Related Airway Inflammatory Response

Aspergillus 단백분해효소 알러젠에 의해 유도된 Th2 관련 기도염증반응에서 protease activated receptor 2 (PAR2)의 역할

  • Yu, Hak-Sun (Department of Parasitology, School of Medicine, Pusan National University)
  • 유학선 (부산대학교 의학전문대학원)
  • Received : 2010.03.13
  • Accepted : 2010.04.19
  • Published : 2010.04.30
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Abstract

Most allergens have protease activities, suggesting that proteases may be a key link between Th2-type immune reactions in allergic responses. Protease activated receptor (PAR) 2 is activated via the proteolytic cleavage of its N-terminal domain by proteinases. To know the role of PAR2 in Aspergillus protease allergen activated Th2 immune responses in airway epithelial cells, we investigated and compared immune cell recruitment and level of chemokines and cytokines between PAR2 knock out (KO) mice and wild type (WT) mice. There were evident immune cell infiltrations into the bronchial alveolar lavage fluid (BALF) of WT mice, but the infiltrations in PAR2 KO mice were significantly lowered than those of WT mice. The IL-25, TSLP, and eotaxin gene expressions were profoundly increased after Aspergillus protease, but their expression was significantly lowered in PAR2 KO mice in this study. Compared to PAR2 KO mice, OVA specific IgE concentrations in serum of WT mice were quite increased; moreover, the IgE level of PAR2 KO mice was lower than in WT mice. The IL-25 expression by Aspergillus protease stimulation was significantly reduced by p38 specific inhibitor treatment. In this study, we determined that Th2 response was initiated with IL-25 and TSLP mRNA up-regulation in lung epithelial cells via PAR2 after Aspergillus protease allergen treatment.

대부분의 알려진 알러젠들은 단백분해효소의 성격을 가지고 있고 이는 알레르기 반응에서 Th2 면역 반응을 일으키는 데 중요한 역할을 하는 것으로 알려져 있다. 이러한 단백분해효소들과 반응하는 것으로 알려진 protease activated receptor (PAR) 는 4가지 종류가 있으며, 이 중 PAR2의 경우 알레르기 질환과 많은 상관관계를 보여 많은 연구가 되고 있다. 본 연구는 Aspergillus protease 알러젠에 의한 초기 및 만성 Th2 면역반응에서 PAR2 의 역할을 규명하기 위해 Aspergillus protease 알러젠으로 정상쥐와 PAR2 유전자 결핍쥐 모두 Th2 반응을 유도한 후 면역세포의 침윤 정도 및 Th2 관련 cytokine 및 chemokine 유전자들의 발현 정도를 비교하였다. 그 결과 Aspergillus protease 알러젠으로 비강내로 1회 처리했을 경우 중성구의 침윤이 두드러지는데, 이때 PAR2 결핍 마우스는 이러한 면역세포의 침윤이 유의적으로 감소하였다. 또한, 이와 관련된 IL-25, TSLP, Eotaxin 유전자들의 발현 역시 PAR2 결핍 마우스에 현저히 감소하였다. 한편, Aspergillus protease 알러젠으로 비강내로 6회 처리했을 경우 중성구 대신 호산구의 침윤이 두드러지지만 PAR2 결핍 마우스에서 그 정도가 유의적으로 낮았다. OVA 특이 IgE와 IgG1 농도 역시 현저하게 PAR2 결핍 마우스에서 낮았고, CCL21의 발현이 PAR2 결핍마우스 MEF cells에서 현저히 감소하였다. Th2 초기 면역반응에서 가장 중요한 IL-25의 발현에 MAKP p38 pathway가 관여한다는 것을 이번 연구에서 알 수 있다. 본 연구를 통해 Aspergillus protease 알러젠으로 유도된 알러지성 기관지 염증 반응에서 초기 반응뿐만 아니라 만성반응에서도 PAR2가 중요한 것을 알 수 있다.

Keywords

References

  1. Al-Shami, A., R. Spolski, J. Kelly, A. Keane-Myers, and W. J. Leonard. 2005. A role for TSLP in the development of inflammation in an asthma model. J. Exp. Med. 202, 829-839. https://doi.org/10.1084/jem.20050199
  2. Alexander, J., G. H. Coombs, and J. C. Mottram. 1998. Leishmania mexicana cysteine proteinase-deficient mutants have attenuated virulence for mice and potentiate a Th1 response. J. Immunol. 161, 6794-6801.
  3. Angkasekwinai, P., H. Park, Y. H. Wang, Y. H. Wang, S. H. Chang, D. B. Corry, Y. J. Liu, Z. Zhu, and C. Dong. 2007. Interleukin 25 promotes the initiation of proallergic type 2 responses. J. Exp. Med. 204, 1509-1517. https://doi.org/10.1084/jem.20061675
  4. Briot, A., C. Deraison, M. Lacroix, C. Bonnart, A. Robin, C. Besson, P. Dubus, and A. Hovnanian. 2009. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J. Exp. Med. 206, 1135-1147. https://doi.org/10.1084/jem.20082242
  5. Comoy, E. E., J. Pestel, C. Duez, G. A. Stewart, C.Vendeville, C. Fournier, F. Finkelman, A. Capron, and G.Thyphronitis. 1998. The house dust mite allergen, Dermatophagoides pteronyssinus, promotes type 2 responses by modulating the balance between IL-4 and IFN-gamma. J. Immunol. 160, 2456-2462.
  6. Cyster, J. G. 1999. Chemokines and cell migration in secondary lymphoid organs. Science. 286, 2098-2102. https://doi.org/10.1126/science.286.5447.2098
  7. Delcroix, M., M. Sajid, C. R. Caffrey, K. C. Lim, J. Dvorak, I. Hsieh, M. Bahgat, C. Dissous, and J. H. McKerrow. 2006. A multienzyme network functions in intestinal protein digestion by a platyhelminth parasite. J. Biol. Chem. 281, 39316-39329. https://doi.org/10.1074/jbc.M607128200
  8. Dixon, H., C. Blanchard, M. L. Deschoolmeester, N. C. Yuill, J. W. Christie, M. E. Rothenberg, and K. J. Else. 2006. The role of Th2 cytokines, chemokines and parasite products in eosinophil recruitment to the gastrointestinal mucosa duringhelminth infection. Eur. J. Immunol. 36, 1753-1763. https://doi.org/10.1002/eji.200535492
  9. Fort, M. M., J. Cheung, D. Yen, J. Li, S. M. Zurawski, S. Lo, S. Menon, T. Clifford, B. Hunte, R. Lesley, T. Muchamuel, S. D. Hurst, G. Zurawski, M. W. Leach, D. M. Gorman, and D. M. Rennick. 2001. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15, 985-995. https://doi.org/10.1016/S1074-7613(01)00243-6
  10. Ganguly, K., S. Upadhyay, M. Irmler, S. Takenaka, K. Pukelsheim, J. Beckers, E. Hamelmann, H. Schulz, and T. Stoeger. 2009. Pathway focused protein profiling indicates differential function for IL-1B, -18 and VEGF during initiationand resolution of lung inflammation evoked by carbon nanoparticle exposure in mice. Part. Fibre. Toxicol. 6, 31. https://doi.org/10.1186/1743-8977-6-31
  11. Hammad, H. and B. N. Lambrecht. 2008. Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma. Nat. Rev. Immunol. 8, 193-204. https://doi.org/10.1038/nri2275
  12. Holzhausen, M., L. C. Spolidorio, and N. Vergnolle. 2005. Role of protease-activated receptor-2 in inflammation, and its possible implications as a putative mediator of periodontitis. Mem. Inst. Oswaldo. Cruz. 100 Suppl 1, 177-180.
  13. Hurst, S. D., T. Muchamuel, D. M. Gorman, J. M. Gilbert, T. Clifford, S. Kwan, S. Menon, B. Seymour, C. Jackson, T. T. Kung, J. K. Brieland, S. M. Zurawski, R. W. Chapman, G. Zurawski, and R. L. Coffman. 2002. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J. Immunol. 169, 443-453. https://doi.org/10.4049/jimmunol.169.1.443
  14. Ikeda, K., H. Nakajima, K. Suzuki, S. Kagami, K. Hirose, A. Suto, Y. Saito, and I. Iwamoto. 2003. Mast cells produce interleukin-25 upon Fc epsilon RI-mediated activation. Blood 101, 3594-3596. https://doi.org/10.1182/blood-2002-09-2817
  15. Kheradmand, F., A. Kiss, J. Xu, S. H. Lee, P. E. Kolattukudy, and D. B. Corry. 2002. A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease. J. Immunol. 169, 5904-5911. https://doi.org/10.4049/jimmunol.169.10.5904
  16. Kiss, A., M. Montes, S. Susarla, E. A. Jaensson, S. M. Drouin, R. A. Wetsel, Z. Yao, R. Martin, N. Hamzeh, R. Adelagun, S. Amar, F. Kheradmand, and D. B. Corry. 2007. A new mechanism regulating the initiation of allergic airway inflammation. J. Allergy Clin. Immunol. 120, 334-342. https://doi.org/10.1016/j.jaci.2007.04.025
  17. Lee, K. E., J. W. Kim, K. Y. Jeong, K. E. Kim, T. S. Yong, and M. H. Sohn. 2007. Regulation of German cockroach extract-induced IL-8 expression in human airway epithelial cells. Clin. Exp. Allergy 37, 1364-1373. https://doi.org/10.1111/j.1365-2222.2007.02797.x
  18. Liu, Y. J., V. Soumelis, N. Watanabe, T. Ito, Y. H. Wang, W. Malefyt Rde, M. Omori, B. Zhou, and S. F. Ziegler. 2007. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu. Rev. Immunol. 25, 193-219. https://doi.org/10.1146/annurev.immunol.25.022106.141718
  19. Miyata, M., K. Hatsushika, T. Ando, N. Shimokawa, Y. Ohnuma, R. Katoh, H. Suto, H. Ogawa, K. Masuyama, and A. Nakao. 2008. Mast cell regulation of epithelial TSLP expression plays an important role in the development of allergic rhinitis. Eur. J. Immunol. 38, 1487-1492. https://doi.org/10.1002/eji.200737809
  20. Omori, M. and S. Ziegler. 2007. Induction of IL-4 expression in CD4(+) T cells by thymic stromal lymphopoietin. J. Immunol. 178, 1396-1404. https://doi.org/10.4049/jimmunol.178.3.1396
  21. Ossovskaya, V. S. and N. W. Bunnett. 2004. Protease-activated receptors: contribution to physiology and disease. Physiol. Rev. 84, 579-621. https://doi.org/10.1152/physrev.00028.2003
  22. Sallusto, F. and A. Lanzavecchia. 2000. Understanding dendritic cell and T-lymphocyte traffic through the analysis of chemokine receptor expression. Immunol. Rev. 177, 134-140. https://doi.org/10.1034/j.1600-065X.2000.17717.x
  23. Shin, S. H., Y. H. Lee, and C. H. Jeon. 2006. Protease-dependent activation of nasal polyp epithelial cells by airborne fungi leads to migration of eosinophils and neutrophils. Acta. Otolaryngol. 126, 1286-1294. https://doi.org/10.1080/00016480500395179
  24. Sokol, C. L., G. M. Barton, A. G. Farr, and R. Medzhitov. 2008. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat. Immunol. 9, 310-318. https://doi.org/10.1038/ni1558
  25. Sun, B. Q., A. Wu, A. Chan, S. Chik, D. Wong, and N. S. Zhong. 2004. House dust mite allergen (Derp1 and Blot5) levels in asthmatics' home in Hongkong. Chin. Med. Sci. J. 19, 185-188.
  26. Takizawa, T., M. Tamiya, T. Hara, J. Matsumoto, N. Saito, T. Kanke, J. Kawagoe, and Y. Hattori. 2005. Abrogation of bronchial eosinophilic inflammation and attenuated eotaxin content in protease-activated receptor 2-deficient mice. J. Pharmacol. Sci. 98, 99-102. https://doi.org/10.1254/jphs.SCZ050138
  27. Traynelis, S. F. and J. Trejo. 2007. Protease-activated receptor signaling: new roles and regulatory mechanisms. Curr. Opin. Hematol. 14, 230-235. https://doi.org/10.1097/MOH.0b013e3280dce568
  28. Wang, Y. H., P. Angkasekwinai, N. Lu, K. S. Voo, K.Arima, S. Hanabuchi, A. Hippe, C. J. Corrigan, C. Dong, B. Homey, Z. Yao, S. Ying, D. P. Huston, and Y. J. Liu. 2007. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J. Exp. Med. 204, 1837-1847. https://doi.org/10.1084/jem.20070406