Airway inflammation is accompanied by infiltration of inflammatory cells and an abnormal response of airway smooth muscle. These cells secrete chemokines and express the cell surface chemokine receptors that play an important role in the migration and degranulation of inflammatory cells. Omalizumab is a monoclonal antibody directed against immunoglobulin E, and its blocking of IgE signaling not only reduces inflammatory cell infiltration mediated by the Th2 immune response but also inhibits other immune responses. The chemokine CCL15 is influenced by omalizumab, and the source of CCL15 has been reported to be airway smooth muscle cells and basophils. CCL15 binds to its receptor CCR1, which has been reported to be expressed by various inflammatory cells and also by airway smooth muscle cells. Therefore, CCL15/CCR1 signaling could be a target for the treatment of asthma. We review the role of CCL15 in the pathogenesis of asthma and also discuss the influence of IgE-mediated immunomodulation via CCL15 and its receptor CCR1. 1. Introduction Chemokines play an important role in the accumulation of inflammatory cells. They belong to a superfamily of small (6–14？kDa) proteins that regulate trafficking in various cells [1]. The C-C motif chemokine ligand 15 (CCL15) is a member of the macrophage inflammatory protein-1 family of chemokines, and its gene is located on 17q11.2. The genetic sequence of CCL15 is similar to that of C-C motif chemokine ligand 5 (CCL5) which is known as regulated on activation normal T cell expressed and secreted (RANTES) and C-C motif chemokine ligand 3 (CCL3), which is named macrophage inflammatory protein-1α (MIP-1α). The CCL15 gene has four exons and three introns. CCL15 has also been variously termed macrophage inhibitory protein-5 (MIP-5), leukotactin-1 (Lkn-1), and human C-C chemokine 2 (HCC-2) [2–4]. CCL15 binds to two receptors known as CCR1 and CCR3, but it has a higher affinity for the former [2, 5, 6]. Although other chemokines, such as CCL3L1 and CCL5, have already been examined in detail to assess their role in asthma, little is known about the possible influence of CCL15 on asthma. Recently, the serum level of CCL15 was found to be elevated in patients with severe asthma and it was shown to be reduced by omalizumab, a humanized anti-IgE antibody [7]. In addition, airway smooth muscle cells (ASMCs) have been shown to produce CCL15 in vitro, and these cells express CCR1 in asthma patients [8, 9]. This paper reviews the role of CCL15 in the pathogenesis of asthma and also discusses the influence of IgE-mediated
References
[1]
F. Sallusto, C. R. Mackay, and A. Lanzavecchia, “The role of chemokine receptors in primary, effector, and memory immune responses,” Annual Review of Immunology, vol. 18, pp. 593–620, 2000.
[2]
F. Coulin, C. A. Power, S. Alouani et al., “Characterisation of macrophage inflammatory protein-5/human CC cytokine-2, a member of the macrophage-inflammatory-protein family of chemokines,” European Journal of Biochemistry, vol. 248, no. 2, pp. 507–515, 1997.
[3]
B. S. Youn, S. M. Zhang, E. K. Lee et al., “Molecular cloning of leukotactin-1: a novel human beta-chemokine, a chemoattractant for neutrophils, monocytes, and lymphocytes, and a potent agonist at CC chemokine receptors 1 and 3,” Journal of Immunology, vol. 159, no. 11, pp. 5201–5205, 1997.
[4]
A. Pardigol, U. Forssmann, H. D. Zucht et al., “HCC-2, a human chemokine: gene structure, expression pattern, and biological activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 11, pp. 6308–6313, 1998.
[5]
J. Ko, I. S. Kim, S. W. Jang et al., “Leukotactin-1/CCL15-induced chemotaxis signaling through CCR1 in HOS cells,” FEBS Letters, vol. 515, no. 1–3, pp. 159–164, 2002.
[6]
U. Forssmann, H. J. M？gert, K. Adermann, S. E. Escher, and W. G. Forssmann, “Hemofiltrate CC chemokines with unique biochemical properties: HCC-1/CCL14a and HCC-2/CCL15,” Journal of Leukocyte Biology, vol. 70, no. 3, pp. 357–366, 2001.
[7]
Y. Shimizu, K. Dobashi, N. Fueki et al., “Changes of immunomodulatory cytokines associated with omalizumab therapy for severe persistent asthma,” Journal of Biological Regulators and Homeostatic Agents, vol. 25, no. 2, pp. 177–186, 2011.
[8]
P. Joubert, S. Lajoie-Kadoch, V. Wellemans et al., “Expression and regulation of CCL15 by human airway smooth muscle cells,” Clinical and Experimental Allergy, vol. 42, no. 1, pp. 85–94, 2012.
[9]
P. Joubert, S. Lajoie-Kadoch, M. Welman et al., “Expression and regulation of CCR1 by airway smooth muscle cells in asthma,” Journal of Immunology, vol. 180, no. 2, pp. 1268–1275, 2008.
[10]
B. S. Youn, S. M. Zhang, H. E. Broxmeyer et al., “Characterization of CKβ8 and CKβ8-1: Two alternatively spliced forms of human β-chemokine, chemoattractants for neutrophils, monocytes, and lymphocytes, and potent agonists at CC chemokine receptor 1,” Blood, vol. 91, no. 9, pp. 3118–3126, 1998.
[11]
S. Zhang, B. S. Youn, J. L. Gao, P. M. Murphy, and B. S. Kwon, “Differential effects of leukotactin-1 and macrophage inflammatory protein-1α on neutrophils mediated by CCR1,” Journal of Immunology, vol. 162, no. 8, pp. 4938–4942, 1999.
[12]
K. Neote, D. DiGregorio, J. Y. Mak, R. Horuk, and T. J. Schall, “Molecular cloning, functional expression, and signaling characteristics of a C-C chemokine receptor,” Cell, vol. 72, no. 3, pp. 415–425, 1993.
[13]
B. L. Daugherty, S. J. Siciliano, J. A. DeMartino, L. Malkowitz, A. Sirotina, and M. S. Springer, “Cloning, expression, and characterization of the human eosinophil eotaxin receptor,” Journal of Experimental Medicine, vol. 183, no. 5, pp. 2349–2354, 1996.
[14]
J. Elsner, S. E. Escher, and U. Forssmann, “Chemokine receptor antagonists: a novel therapeutic approach in allergic diseases,” Allergy, vol. 59, no. 12, pp. 1243–1258, 2004.
[15]
C. Combadiere, S. K. Ahuja, and P. M. Murphy, “Cloning, chromosomal localization, and RNA expression of a human β chemokine receptor-like gene,” DNA and Cell Biology, vol. 14, no. 8, pp. 673–680, 1995.
[16]
K. Amin, C. Janson, I. Harvima, P. Venge, and G. Nilsson, “CC chemokine receptors CCR1 and CCR4 are expressed on airway mast cells in allergic asthma,” Journal of Allergy and Clinical Immunology, vol. 116, no. 6, pp. 1383–1386, 2005.
[17]
R. Saunders, A. Sutcliffe, D. Kaur et al., “Airway smooth muscle chemokine receptor expression and function in asthma,” Clinical and Experimental Allergy, vol. 39, no. 11, pp. 1684–1692, 2009.
[18]
J. S. Lee and I. S. Kim, “Leukotactin-1/CCL15 induces cell migration and differentiation of human eosinophilic leukemia EoL-1 cells through PKCδ activation,” Molecular Biology Reports, vol. 37, no. 5, pp. 2149–2156, 2010.
[19]
J. Ko, C. Y. Yun, J. S. Lee, J. H. Kim, and S. K. In, “p38 MAPK and ERK activation by 9-cis-retinoic acid induces chemokine receptors CCR1 and CCR2 expression in human monocytic THP-1 cells,” Experimental and Molecular Medicine, vol. 39, no. 2, pp. 129–138, 2007.
[20]
R. Saunders, A. Sutcliffe, L. Woodman et al., “The airway smooth muscle CCR3/CCL11 axis is inhibited by mast cells,” Allergy, vol. 63, no. 9, pp. 1148–1155, 2008.
[21]
G. T. Kampen, S. Stafford, T. Adachi et al., “Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases,” Blood, vol. 95, no. 6, pp. 1911–1917, 2000.
[22]
M. E. Bates, J. B. Sedgwick, Y. Zhu et al., “Human airway eosinophils respond to chemoattractants with greater eosinophil-derived neurotoxin release, adherence to fibronectin, and activation of the ras-ERK pathway when compared with blood eosinophils,” Journal of Immunology, vol. 184, no. 12, pp. 7125–7133, 2010.
[23]
S. Matsukura, M. Odaka, M. Kurokawa et al., “Transforming growth factor-β stimulates the expression of eotaxin/CC chemokine ligand 11 and its promoter activity through binding site for nuclear factor-κB in airway smooth muscle cells,” Clinical and Experimental Allergy, vol. 40, no. 5, pp. 763–771, 2010.
[24]
R. Bonecchi, G. Bianchi, P. P. Bordignon et al., “Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s,” Journal of Experimental Medicine, vol. 187, no. 1, pp. 129–134, 1998.
[25]
J. L. Gao, T. A. Wynn, Y. Chang et al., “Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1,” Journal of Experimental Medicine, vol. 185, no. 11, pp. 1959–1968, 1997.
[26]
A. Arakelyan, E. Kriegova, Z. Kubi？tova et al., “Protein levels of CC chemokine ligand (CCL)15, CCL16 and macrophage stimulating protein in patients with sarcoidosis,” Clinical and Experimental Immunology, vol. 155, no. 3, pp. 457–465, 2009.
[27]
K. L. Reckamp, B. K. Gardner, R. A. Figlin et al., “Tumor response to combination celecoxib and erlotinib therapy in non-small cell lung cancer is associated with a low baseline matrix metalloproteinase-9 and a decline in serum-soluble E-cadherin,” Journal of Thoracic Oncology, vol. 3, no. 2, pp. 117–124, 2008.
[28]
L. Gilmartin, C. A. Tarleton, M. Schuyler, B. S. Wilson, and J. M. Oliver, “A comparison of inflammatory mediators released by basophils of asthmatic and control subjects in response to high-affinity ige receptor aggregation,” International Archives of Allergy and Immunology, vol. 145, no. 3, pp. 182–192, 2008.
[29]
R. M. Phillips, V. E. L. Stubbs, M. R. Henson, T. J. Williams, J. E. Pease, and I. Sabroe, “Variations in eosinophil chemokine responses: An investigation of CCR1 and CCR3 function, expression in atopy, and identification of a functional CCR1 promoter,” Journal of Immunology, vol. 170, no. 12, pp. 6190–6201, 2003.
[30]
M. Souhrada and J. F. Souhrada, “Immunologically induced alterations of airway smooth muscle cell membrane,” Science, vol. 225, no. 4663, pp. 723–725, 1984.
[31]
A. S. Gounni, V. Wellemans, J. Yang et al., “Human airway smooth muscle cells express the high affinity receptor for IgE (FcεRI): a critical role of FcεRI in human airway smooth muscle cell function,” Journal of Immunology, vol. 175, no. 4, pp. 2613–2621, 2005.
[32]
H. Hakonarson and M. M. Grunstein, “Autologously up-regulated Fc receptor expression and action in airway smooth muscle mediates its altered responsiveness in the atopic asthmatic sensitized state,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 9, pp. 5257–5262, 1998.
[33]
M. Roth and M. Tamm, “The effects of omalizumab on IgE-induced cytokine synthesis by asthmatic airway smooth muscle cells,” Annals of Allergy, Asthma and Immunology, vol. 104, no. 2, pp. 152–160, 2010.
[34]
A. A. Litonjua, D. Sparrow, L. Guevarra, G. T. O'Connor, S. T. Weiss, and D. J. Tollerud, “Serum interferon-γ is associated with longitudinal decline in lung function among asthmatic patients: the Normative Aging Study,” Annals of Allergy, Asthma and Immunology, vol. 90, no. 4, pp. 422–428, 2003.
[35]
J. Shannon, P. Ernst, Y. Yamauchi et al., “Differences in airway cytokine profile in severe asthma compared to moderate asthma,” Chest, vol. 133, no. 2, pp. 420–426, 2008.
[36]
K. Oboki, T. Ohno, H. Saito, and S. Nakae, “Th17 and allergy,” Allergology International, vol. 57, no. 2, pp. 121–134, 2008.
[37]
P. M. Hansbro, G. E. Kaiko, and P. S. Foster, “Cytokine/anti-cytokine therapy—novel treatments for asthma?” British Journal of Pharmacology, vol. 163, no. 1, pp. 81–95, 2011.
[38]
T. Sugimoto, Y. Ishikawa, T. Yoshimoto, N. Hayashi, J. Fujimoto, and K. Nakanishi, “Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse,” Journal of Experimental Medicine, vol. 199, no. 4, pp. 535–545, 2004.
[39]
K. Nakanishi, H. Tsutsui, and T. Yoshimoto, “Importance of IL-18-induced super Th1 cells for the development of allergic inflammation,” Allergology International, vol. 59, no. 2, pp. 137–141, 2010.
[40]
J. A. Wisniewski and L. Borish, “Novel cytokines and cytokine-producing T cells in allergic disorders,” Allergy and Asthma Proceedings, vol. 32, no. 2, pp. 83–94, 2011.
[41]
C. Vock, H. P. Hauber, and M. Wegmann, “The other T helper cells in asthma pathogenesis,” Journal of Allergy, Article ID 519298, 14 pages, 2010.
[42]
L. Zhou, I. I. Ivanov, R. Spolski et al., “IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways,” Nature Immunology, vol. 8, no. 9, pp. 967–974, 2007.
[43]
P. Soroosh and T. A. Doherty, “Th9 and allergic disease,” Immunology, vol. 127, no. 4, pp. 450–458, 2009.
[44]
S. Baraldo, D. S. Faffe, P. E. Moore et al., “Interleukin-9 influences chemokine release in airway smooth muscle: Role of ERK,” American Journal of Physiology, vol. 284, no. 6, pp. L1093–L1102, 2003.
[45]
M. Braga, C. Quecchia, E. Cavallucci et al., “T regulatory cells in allergy,” International journal of immunopathology and pharmacology, vol. 24, no. 1, pp. S55–S64, 2011.
[46]
M. V. Kopp, S. Stenglein, W. Kamin et al., “Omalizumab (Xolair) in children with seasonal allergic rhinitis: leukotriene release as a potential in vitro parameter to monitor therapeutic effects,” Pediatric Allergy and Immunology, vol. 18, no. 6, pp. 523–527, 2007.
[47]
J. A. Eckman, P. M. Sterba, D. Kelly et al., “Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge,” Journal of Allergy and Clinical Immunology, vol. 125, no. 4, pp. 889–e7, 2010.
[48]
P. Vichyanond, “Omalizumab in allergic diseases, a recent review,” Asian Pacific Journal of Allergy & Immunology, vol. 29, no. 3, pp. 209–219, 2011.
[49]
J. Bousquet, S. Wenzel, S. Holgate, W. Lumry, P. Freeman, and H. Fox, “Predicting response to omalizumab, an anti-IgE antibody, in patients with allergic asthma,” Chest, vol. 125, no. 4, pp. 1378–1386, 2004.
[50]
M. Hoshino and J. Ohtawa, “Effects of adding omalizumab, an anti-immunoglobulin E antibody, on airway wall thickening in asthma,” Respiration, vol. 83, no. 6, pp. 520–528, 2012.
[51]
S. H. Kwon, S. A. Ju, J. H. Kang, C. S. Kim, H. M. Yoo, and R. Yu R, “Chemokine Lkn-1/CCL15 enhances matrix metalloproteinase-9 release from human macrophages and macrophage-derived foam cells,” Nutrition Research and Practice, vol. 2, no. 2, pp. 134–137, 2008.
[52]
M. Humbert, R. Beasley, J. Ayres et al., “Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE,” Allergy, vol. 60, no. 3, pp. 309–316, 2005.
[53]
S. T. Holgate, A. G. Chuchalin, J. Hébert et al., “Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma,” Clinical and Experimental Allergy, vol. 34, no. 4, pp. 632–638, 2004.
[54]
K. Ohta, T. Miyamoto, T. Amagasaki, and M. Yamamoto, “Efficacy and safety of omalizumab in an Asian population with moderate-to-severe persistent asthma,” Respirology, vol. 14, no. 8, pp. 1156–1165, 2009.
[55]
A. A. Long, J. E. Fish, A. Rahmaoui et al., “Baseline characteristics of patients enrolled in EXCELS: a cohort study,” Annals of Allergy, Asthma and Immunology, vol. 103, no. 3, pp. 212–219, 2009.
[56]
M. D. Eisner, J. L. Zazzali, M. K. Miller, M. S. Bradley, and M. Schatz, “Longitudinal changes in asthma control with omalizumab: 2-year interim data from the EXCELS Study,” Journal of Asthma, vol. 49, no. 6, pp. 642–628, 2012.
[57]
J. T. Schroeder, A. P. Bieneman, K. L. Chichester et al., “Decreases in human dendritic cell-dependent TH2-like responses after acute in vivo IgE neutralization,” Journal of Allergy and Clinical Immunology, vol. 125, no. 4, article e6, pp. 896–901, 2010.
