Agonist Activity of the Small Molecule C3aR Ligand SB 290157
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免疫学杂志 2005年第12期
There has been a recent surge of interest in the literature for the anaphylatoxins C3a and C5a and their role in inflammatory diseases. While knockout studies have provided important information regarding the role of C3a in allergic diseases such as asthma (1, 2), the publication of a potent small molecule antagonist of the C3a receptor, SB 290157, offered the possibility of confirming C3a-specific events in animal models of disease without the provisos normally associated with genetically modified organisms (3). Indeed, a number of studies have recently taken advantage of the availability of SB 290157 to ascribe roles to C3a, or refute such roles, in a variety of disease models (4, 5, 6, 7, 8). One case in point is the recent article in The Journal of Immunology by Baelder et al. (4) showing that C3a does not have an important role in the pathogenesis of airway hyperreactivity (AHR) in a murine allergen-induced model of asthma. The findings presented in that study, based on the lack of an SB 290157-dependent effect on AHR, contradict previous observations in C3aR-knockout mice (1, 2). Interestingly, not only did SB 290157 fail to protect mice against allergen-induced AHR, but the authors also observed an SB 290157-dependent increase in AHR in the context of C5aR blockade.
Our group has recently obtained data explaining this discrepancy and cautioning against the use of SB 290157 as a tool to investigate C3a-related effects (9). Indeed, while SB 290157 acts as an antagonist in a cellular system where receptor density is low, the compound is a full agonist of C3aR in cell lines that express higher levels of C3aR, consistent with SB 290157 being a partial agonist of C3aR. Since C3aR levels are increased in smooth muscle cells in an allergen-challenge model of asthma (10), the possibility exists that SB 290157 can activate, rather than antagonize, C3aR in the model used by Baelder et al. A role of C3a in AHR should therefore not be discounted based on the findings in the otherwise important study by Baelder and colleagues.
References
Drouin, S. M., D. B. Corry, T. J. Hollman, J. Kildsgaard, R. A. Wetsel. 2002. Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J. Immunol. 169: 5926-5933.
Humbles, A. A., B. Lu, C. A. Nilsson, C. Lilly, E. Israel, Y. Fujiwara, N. P. Gerard, C. Gerard. 2000. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 406: 998-1001.
Ames, R. S., D. Lee, J. J. Foley, A. J. Jurewicz, M. A. Tornetta, W. Bautsch, B. Settmacher, A. Klos, K. F. Erhard, R. D. Cousins, et al 2001. Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models. J. Immunol. 166: 6341-6348.
Baelder, R., B. Fuchs, W. Bautsch, J. Zwirner, J. K?hl, H. G. Hoymann, T. Glaab, V. Erpenbeck, N. Krug, A. Braun. 2005. Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation. J. Immunol. 174: 783-789.
Godau, J., T. Heller, H. Hawlisch, M. Trappe, E. Howells, J. Best, J. Zwirner, J. S. Verbeek, P. M. Hogarth, C. Gerard, et al 2004. C5a initiates the inflammatory cascade in immune complex peritonitis. J. Immunol. 173: 3437-3445.
Mollnes, T. E., O. L. Brekke, M. Fung, H. Fure, D. Christiansen, G. Bergseth, V. Videm, K. T. Lappegard, J. Kohl, J. D. Lambris. 2002. Essential role of the C5a receptor in E. coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. Blood 100: 1869-1877.
Proctor, L. M., T. V. Arumugam, I. Shiels, R. C. Reid, D. P. Fairlie, S. M. Taylor. 2004. Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury. Br. J. Pharmacol. 142: 756-764.
Ratajczak, J., R. Reca, M. Kucia, M. Majka, D. J. Allendorf, J. T. Baran, A. Janowska-Wieczorek, R. A. Wetsel, G. D. Ross, M. Z. Ratajczak. 2004. Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow. Blood 103: 2071-2078.
Mathieu, M.-C., N. Sawyer, G. M. Greig, M. Hamel, S. Kargman, Y. Ducharme, C. K. Lau, R. W.(Alex G. Therien)
Our group has recently obtained data explaining this discrepancy and cautioning against the use of SB 290157 as a tool to investigate C3a-related effects (9). Indeed, while SB 290157 acts as an antagonist in a cellular system where receptor density is low, the compound is a full agonist of C3aR in cell lines that express higher levels of C3aR, consistent with SB 290157 being a partial agonist of C3aR. Since C3aR levels are increased in smooth muscle cells in an allergen-challenge model of asthma (10), the possibility exists that SB 290157 can activate, rather than antagonize, C3aR in the model used by Baelder et al. A role of C3a in AHR should therefore not be discounted based on the findings in the otherwise important study by Baelder and colleagues.
References
Drouin, S. M., D. B. Corry, T. J. Hollman, J. Kildsgaard, R. A. Wetsel. 2002. Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy. J. Immunol. 169: 5926-5933.
Humbles, A. A., B. Lu, C. A. Nilsson, C. Lilly, E. Israel, Y. Fujiwara, N. P. Gerard, C. Gerard. 2000. A role for the C3a anaphylatoxin receptor in the effector phase of asthma. Nature 406: 998-1001.
Ames, R. S., D. Lee, J. J. Foley, A. J. Jurewicz, M. A. Tornetta, W. Bautsch, B. Settmacher, A. Klos, K. F. Erhard, R. D. Cousins, et al 2001. Identification of a selective nonpeptide antagonist of the anaphylatoxin C3a receptor that demonstrates antiinflammatory activity in animal models. J. Immunol. 166: 6341-6348.
Baelder, R., B. Fuchs, W. Bautsch, J. Zwirner, J. K?hl, H. G. Hoymann, T. Glaab, V. Erpenbeck, N. Krug, A. Braun. 2005. Pharmacological targeting of anaphylatoxin receptors during the effector phase of allergic asthma suppresses airway hyperresponsiveness and airway inflammation. J. Immunol. 174: 783-789.
Godau, J., T. Heller, H. Hawlisch, M. Trappe, E. Howells, J. Best, J. Zwirner, J. S. Verbeek, P. M. Hogarth, C. Gerard, et al 2004. C5a initiates the inflammatory cascade in immune complex peritonitis. J. Immunol. 173: 3437-3445.
Mollnes, T. E., O. L. Brekke, M. Fung, H. Fure, D. Christiansen, G. Bergseth, V. Videm, K. T. Lappegard, J. Kohl, J. D. Lambris. 2002. Essential role of the C5a receptor in E. coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. Blood 100: 1869-1877.
Proctor, L. M., T. V. Arumugam, I. Shiels, R. C. Reid, D. P. Fairlie, S. M. Taylor. 2004. Comparative anti-inflammatory activities of antagonists to C3a and C5a receptors in a rat model of intestinal ischaemia/reperfusion injury. Br. J. Pharmacol. 142: 756-764.
Ratajczak, J., R. Reca, M. Kucia, M. Majka, D. J. Allendorf, J. T. Baran, A. Janowska-Wieczorek, R. A. Wetsel, G. D. Ross, M. Z. Ratajczak. 2004. Mobilization studies in mice deficient in either C3 or C3a receptor (C3aR) reveal a novel role for complement in retention of hematopoietic stem/progenitor cells in bone marrow. Blood 103: 2071-2078.
Mathieu, M.-C., N. Sawyer, G. M. Greig, M. Hamel, S. Kargman, Y. Ducharme, C. K. Lau, R. W.(Alex G. Therien)