ABSTRACT
Title
The ocular antiallergic action of mapracorat, a novel selective glucocorticoid receptor agonist, involves eosinophils and mast cells: evidence from human cells in vitro and an animal model
Authors
M. Baiula1, A. Spartà2, A. Bedini1, G. Carbonari1, C. Bucolo3, K.W. Ward4, J-Z. Zhang4, P. Govoni5, S. Spampinato1
1Dept. of Pharmacology, University of Bologna, Bologna, Italy
2Centre for Integrative Biology (CiBIO),University of Trento, Italy
3Dept. of Pharmacology, University of Catania, Catania, Italy
4Pharmaceutical Research & Development, Bausch & Lomb, Rochester, NY, USA
5Dept. of Experimental Medicine - Section of Histology, University of Parma, Italy
1Dept. of Pharmacology, University of Bologna, Bologna, Italy
2Centre for Integrative Biology (CiBIO),University of Trento, Italy
3Dept. of Pharmacology, University of Catania, Catania, Italy
4Pharmaceutical Research & Development, Bausch & Lomb, Rochester, NY, USA
5Dept. of Experimental Medicine - Section of Histology, University of Parma, Italy
Abstract
Allergic eye diseases are usually associated with type 1 hypersensitivity reactions, which cause early- and late-phase responses. Clinical symptoms and signs such as itching, chemosis, and congestion, driven primarily by mast cell degranulation, are manifested very quickly. This is followed by the late-phase response after 6-24 h, which involves eosinophil and neutrophil infiltration into the conjunctiva (Leonardi et al., 2008). Inflammatory cells, cytokines and proteases contribute to more serious chronic forms (Miyazaki et al., 2008). Glucocorticoids are among the most effective drugs for the treatment of allergic eye disease (Ono and Abelson, 2005). Their efficacy lies, among other things, in the direct induction of eosinophil apoptosis, suppression of the synthesis and release of eosinophil survival factors and stimulation of their engulfment by phagocytic cells (Druilhe et al., 2003). Unfortunately, their anti-inflammatory and immunosuppressive effects are frequently accompanied by undesired side effects that may limit their use.
The most widely investigated effects of glucocorticoids on target cells involve the regulation of transcription of steroid-responsive genes as a consequence of their penetrating the cytoplasm and binding to the glucocorticoid receptor; then the glucocorticoid-glucocorticoid receptor complex reaches the nucleus and acts as a transcription factor binding to specific DNA sites in the nucleus. This can have two effects on gene transcription: it can either activate transcription (transactivation) by directly binding to the promoter region of target genes or, by interacting with other transcription factors such as activator protein-1 (AP-1), nuclear factor κB (NF-κB) and others, it can suppress transcription (transrepression) (Biddie and Hager, 2009). The latter is considered the key mechanism for the anti-inflammatory activity (Catley, 2007; Zhang et al., 2009).
A better understanding of the molecular mode of glucocorticoid action has led to the identification of novel selective glucocorticoid receptor agonists (SEGRA) that should preserve the beneficial anti-inflammatory activity but offer a better side-effect profile (McMaster and Ray, 2008).
Mapracorat (also known as BOL-303242-X or ZK 245186) is the latest in this development. It displays topical anti-inflammatory activity but is less effective in transactivation and, therefore, has less potential for side effects. To date, the potential antiallergic activity of mapracorat in the eye and whether eosinophils and mast cells are targets of its action has been explored very little. We investigated its effects in vitro on human eosinophil functions and cytokine and chemokine secretion by the human mast cell line HMC-1 and in vivo in a model of allergic conjunctivitis. Mapracorat binds to the glucocorticoid receptor and shows the same potency as dexamethasone, but displayed higher efficacy in increasing spontaneous eosinophil apoptosis and in counteracting cytokine-sustained eosinophil survival. It inhibited cytokine and chemokine release by eosinophils and mast cells in vitro, with equal potency as dexamethasone, but it was less potent than this glucocorticoid in inducing annexin I and CXCR4 receptor expression on the eosinophil surface, which is taken as a possible sign of glucocorticoid-dependent transactivation. In the guinea-pig, mapracorat or dexamethasone eye drops induce an analogous reduction in clinical symptoms of allergic conjunctivitis and conjunctival eosinophil infiltration.
Leonardi et al.(2008) Clin Exp Immunol 153(Suppl 1): 17-21.
Miyazaki et al. (2008) Mol Vis14: 1525-1532.
Ono and Abelson (2005) J Allergy Clin Immunol 115: 118-122.
Druilhe et al. (2003). Apoptosis 8: 481-495.
Biddie and Hager (2009). Stress 12: 193-205.
Catley (2007). ScientificWorldJournal. 7: 421-430.
Zhang et al. (2009). Mol Vis. 15: 2606-2616.
McMaster and Ray (2008). Nat Clin Pract Endocrinol Metab. 4: 91-101.
Qasem et al. (2008) Biochem Pharm 76:751-762.
The most widely investigated effects of glucocorticoids on target cells involve the regulation of transcription of steroid-responsive genes as a consequence of their penetrating the cytoplasm and binding to the glucocorticoid receptor; then the glucocorticoid-glucocorticoid receptor complex reaches the nucleus and acts as a transcription factor binding to specific DNA sites in the nucleus. This can have two effects on gene transcription: it can either activate transcription (transactivation) by directly binding to the promoter region of target genes or, by interacting with other transcription factors such as activator protein-1 (AP-1), nuclear factor κB (NF-κB) and others, it can suppress transcription (transrepression) (Biddie and Hager, 2009). The latter is considered the key mechanism for the anti-inflammatory activity (Catley, 2007; Zhang et al., 2009).
A better understanding of the molecular mode of glucocorticoid action has led to the identification of novel selective glucocorticoid receptor agonists (SEGRA) that should preserve the beneficial anti-inflammatory activity but offer a better side-effect profile (McMaster and Ray, 2008).
Mapracorat (also known as BOL-303242-X or ZK 245186) is the latest in this development. It displays topical anti-inflammatory activity but is less effective in transactivation and, therefore, has less potential for side effects. To date, the potential antiallergic activity of mapracorat in the eye and whether eosinophils and mast cells are targets of its action has been explored very little. We investigated its effects in vitro on human eosinophil functions and cytokine and chemokine secretion by the human mast cell line HMC-1 and in vivo in a model of allergic conjunctivitis. Mapracorat binds to the glucocorticoid receptor and shows the same potency as dexamethasone, but displayed higher efficacy in increasing spontaneous eosinophil apoptosis and in counteracting cytokine-sustained eosinophil survival. It inhibited cytokine and chemokine release by eosinophils and mast cells in vitro, with equal potency as dexamethasone, but it was less potent than this glucocorticoid in inducing annexin I and CXCR4 receptor expression on the eosinophil surface, which is taken as a possible sign of glucocorticoid-dependent transactivation. In the guinea-pig, mapracorat or dexamethasone eye drops induce an analogous reduction in clinical symptoms of allergic conjunctivitis and conjunctival eosinophil infiltration.
Leonardi et al.(2008) Clin Exp Immunol 153(Suppl 1): 17-21.
Miyazaki et al. (2008) Mol Vis14: 1525-1532.
Ono and Abelson (2005) J Allergy Clin Immunol 115: 118-122.
Druilhe et al. (2003). Apoptosis 8: 481-495.
Biddie and Hager (2009). Stress 12: 193-205.
Catley (2007). ScientificWorldJournal. 7: 421-430.
Zhang et al. (2009). Mol Vis. 15: 2606-2616.
McMaster and Ray (2008). Nat Clin Pract Endocrinol Metab. 4: 91-101.
Qasem et al. (2008) Biochem Pharm 76:751-762.