Thymic Stromal Lymphopoietin Expression Is Increased in Asthmatic Airways and Correlates with Expression of Th2-Attracting Chemokines and Disease Severity
Tóm tắt
Thymic stromal lymphopoietin (TSLP) is said to increase expression of chemokines attracting Th2 T cells. We hypothesized that asthma is characterized by elevated bronchial mucosal expression of TSLP and Th2-attracting, but not Th1-attracting, chemokines as compared with controls, with selective accumulation of cells bearing receptors for these chemokines. We used in situ hybridization and immunohistochemistry to examine the expression and cellular provenance of TSLP, Th2-attracting (thymus and activation-regulated chemokine (TARC)/CCL17, macrophage-derived chemokine (MDC)/CCL22, I-309/CCL1) and Th1-attracting (IFN-γ-inducible protein 10 (IP-10)/CXCL10, IFN-inducible T cell α-chemoattractant (I-TAC)/CXCL11) chemokines and expression of their receptors CCR4, CCR8, and CXCR3 in bronchial biopsies from 20 asthmatics and 15 normal controls. The numbers of cells within the bronchial epithelium and submucosa expressing mRNA for TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in asthmatics as compared with controls (p ≤ 0.018). TSLP and TARC/CCL17 expression correlated with airway obstruction. Although the total numbers of cells expressing CCR4, CCR8, and CXCR3 did not significantly differ in the asthmatics and controls, there was evidence of selective infiltration of CD4+/CCR4+ T cells in the asthmatic biopsies which correlated with TARC and MDC expression and airway obstruction. Epithelial cells, endothelial cells, neutrophils, macrophages, and mast cells were significant sources of TSLP and chemokines. Our data implicate TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10 in asthma pathogenesis. These may act partly through selective development and retention, or recruitment of Th2 cells bearing their receptors.
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Luster, A. D.. 2002. The role of chemokines in linking innate and adaptive immunity. Curr. Opin. Immunol. 14: 129-135.
D’Ambrosio, D., A. Iellem, R. Bonecchi, D. Mazzeo, S. Sozzani, A. Mantovani, F. Sinigaglia. 1998. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. J. Immunol. 161: 5111-5115.
Sallusto, F., D. Lenig, C. R. Mackay, A. Lanzavecchia. 1998. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J. Exp. Med. 187: 875-883.
Panina-Bordignon, P., A. Papi, M. Mariani, P. Di Lucia, G. Casoni, C. Bellettato, C. Buonsanti, D. Miotto, C. Mapp, A. Villa, et al 2001. The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics. J. Clin. Invest. 107: 1357-1364.
Nouri-Aria, K. T., D. Wilson, J. N. Francis, L. A. Jopling, M. R. Jacobson, M. R. Hodge, D. P. Andrew, S. J. Till, E. M. Varga, T. J. Williams, et al 2002. CCR4 in human allergen-induced late responses in the skin and lung. Eur. J. Immunol. 32: 1933-1938.
Kunkel, E. J., J. Boisvert, K. Murphy, M. A. Vierra, M. C. Genovese, A. J. Wardlaw, H. B. Greenberg, M. R. Hodge, L. Wu, E. C. Butcher, J. J. Campbell. 2002. Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes. Am. J. Pathol. 160: 347-355.
Soumelis, V., P. A. Reche, H. Kanzler, W. Yuan, G. Edward, B. Homey, M. Gilliet, S. Ho, S. Antonenko, A. Lauerma, et al 2002. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3: 605-607.
Ying, S., Q. Meng, K. Zeibecoglou, D. S. Robinson, A. Macfarlane, M. Humbert, A. B. Kay. 1999. Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, MCP-3, and MCP-4) and CCR3 expression in bronchial biopsies from atopic and non-atopic (intrinsic) asthma. J. Immunol. 163: 6321-6329.
Imai, T., T. Yoshida, M. Baba, M. Nishimura, M. Kakizaki, O. Yoshie. 1996. Molecular cloning of a novel T cell-directed CC chemokine expression in thymus by signal sequence trap using Epstein-Barr virus vector. J. Biol. Chem. 271: 21514-21521.
Godiska, R., D. Chantry, C. J. Raport, S. Sozzani, P. Allavena, D. Leviten, A. Mantovani, P. W. Gray. 1997. Human macrophage-derived chemokine (MDC), a novel chemoattractant for monocytes, monocytes-derived dendritic cells, and natural killer cells. J. Exp. Med. 185: 1595-1604.
Quentmeier, H., H. G. Drexler, D. Fleckenstein, M. Zaborski, A. Armstrong, J. E. Sims, S. D. Lyman. 2001. Cloning of human thymic stromal lymphopoietin (TSLP) and signaling mechanisms leading to proliferation. Leukemia 15: 1286-1292.
Sarris, A. H., H. E. Broxmeyer, U. Wirthmueller, N. Karasavvas, S. Cooper, L. Lu, J. Krueger, J. V. Ravetch. 1993. Human interferon-inducible protein 10: expression and purification of recombinant protein demonstrate inhibition of early human hematopoietic progenitors. J. Exp. Med. 178: 1127-1132.
Cole, K. E., C. A. Strick, T. J. Paradis, K. T. Ogborne, M. Loetscher, R. P. Gladue, W. Lin, J. G. Boyd, B. Moser, D. E. Wood, et al 1998. Interferon-inducible T cell α chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3. J. Exp. Med. 187: 2009-2021.
Miller, M. D., S. Hata, R. De Waal Malefyt, M. S. Krangel. 1989. A novel polypeptide secreted by activated human T lymphocytes. J. Immunol. 143: 2907-2916.
Moqbel, R., J. Barkans, B. L. Bradley, S. R. Durham, A. B. Kay. 1992. Application of monoclonal antibodies against major basic protein (BMK-13) and eosinophil cationic protein (EG1 and EG2) for quantifying eosinophils in bronchial biopsies from atopic asthma. Clin. Exp. Allergy 22: 265-273.
Bochner, B. S., S. A. Hudson, H. Q. Xiao, M. C. Liu. 2003. Release of both CCR4-active and CXCR3-active chemokines during human allergic pulmonary late-phase reactions. J. Allergy Clin. Immunol. 112: 930-934.
Sekiya, T., H. Yamada, M. Yamaguchi, K. Yamamoto, A. Ishii, O. Yoshie, Y. Sano, A. Morita, K. Matsushima, K. Hirai. 2002. Increased levels of a TH2-type CC chemokine thymus and activation-regulated chemokine (TARC) in serum and induced sputum of asthmatics. Allergy 57: 173-177.
Lezcano-Meza, D., M. C. Negrete-Garcia, M. Dante-Escobedo, L. M. Teran. 2003. The monocyte-derived chemokine is released in the bronchoalveolar lavage fluid of steady-state asthmatics. Allergy 58: 1125-1130.
Miotto, D., P. Christodoulopoulos, R. Olivenstein, R. Taha, L. Cameron, A. Tsicopoulos, A. B. Tonnel, O. Fahy, J. J. Lafitte, A. D. Luster, et al 2001. Expression of IFN-γ-inducible protein; monocyte chemotactic proteins 1, 3, and 4; and eotaxin in TH1- and TH2-mediated lung diseases. J. Allergy Clin. Immunol. 107: 664-670.
Kawasaki, S., H. Takizawa, H. Yoneyama, T. Nakayama, R. Fujisawa, M. Izumizaki, T. Imai, O. Yoshie, I. Homma, K. Yamamoto, K. Matsushima. 2001. Intervention of thymus and activation-regulated chemokine attenuates the development of allergic airway inflammation and hyperresponsiveness in mice. J. Immunol. 166: 2055-2062.
Gonzalo, J. A., Y. Pan, C. M. Lloyd, G. Q. Jia, G. Yu, B. Dussault, C. A. Powers, A. E. Proudfoot, A. J. Coyle, D. Gearing, J. C. Gutierrez-Ramos. 1999. Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation. J. Immunol. 163: 403-411.
Medoff, B. D., A. Sauty, A. M. Tager, J. A. Maclean, R. N. Smith, A. Mathew, J. H. Dufour, A. D. Luster. 2002. IFN-γ-inducible protein 10 (CXCL10) contributes to airway hyperreactivity and airway inflammation in a mouse model of asthma. J. Immunol. 168: 5278-5286.
Leckie, M. J., A. ten Brinke, J. Khan, Z. Diamant, B. J. O’Connor, C. M. Walls, A. K. Mathur, H. C. Cowley, K. F. Chung, R. Djukanovic, et al 2000. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 356: 2144-2148.
Belperio, J. A., M. Dy, L. Murray, M. D. Burdick, Y. Y. Xue, R. M. Strieter, M. P. Keane. 2004. The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis. J. Immunol. 173: 4692-4698.
Message, S. D., S. L. Johnston. 2004. Host defense function of the airway epithelium in health and disease: clinical background. J. Leukocyte Biol. 75: 5-17.
Sekiya, T., M. Miyamasu, M. Imanishi, H. Yamada, T. Nakajima, M. Yamaguchi, T. Fujisawa, R. Pawankar, Y. Sano, K. Ohta, et al 2000. Inducible expression of a Th2-type CC chemokine thymus- and activation-regulated chemokine by human bronchial epithelial cells. J. Immunol. 165: 2205-2213.