Pharmacological Modulation of Caspase-8 in Thymus-Related Medical Conditions

Abstract

The thymus is a lymphoid organ that governs the development of a diverse T-cell repertoire capable of defending against nonselfantigens and avoiding autoimmunity. However, the thymus can also succumb to different diseases. Hypertrophic diseases, such as thymomas, are typically associated with impairment of negative selection, which leads to autoimmune disease, or disruption of positive selection, which results in immunodeficiency. Hypotrophic diseases of the thymus can manifest during acute infections, cancer, allogeneic bone marrow transplantation, or with aging. This condition leads to decreased immune function and can be treated by either replacing lost thymic tissue or by preventing thymic tissue death. Studies have demonstrated the critical role of caspase-8 in regulating apoptosis in the thymus. In this review, we discuss how pharmacological activation and inhibition of caspase-8 can be used to treat hypertrophic and hypotrophic diseases of the thymus, respectively, to improve its function.

Acute Thymic Involution and Mechanisms for Recovery

“…The administration of JWH-015, a synthetic CB2-selective agonist, has also been implicated as a cause of enhanced thymic apoptosis and ATI (Eisenstein and Meissler 2015;Lombard et al 2007). Terfenadine (an antiallergy drug) causes thymocyte death through a mitochondrial pathway and results in a remarkable increase in DNA fragmentation and the activation of certain caspases in rats (Enomoto et al 2004;Pozzesi et al 2014). Methamphetamine administration in a rodent model promotes apoptosis through caspase-9 activation and diminishes the thymic cellularity (Fujikawa et al 2007;Peerzada et al 2013;Pozzesi et al 2014).…”

“…Terfenadine (an antiallergy drug) causes thymocyte death through a mitochondrial pathway and results in a remarkable increase in DNA fragmentation and the activation of certain caspases in rats (Enomoto et al 2004;Pozzesi et al 2014). Methamphetamine administration in a rodent model promotes apoptosis through caspase-9 activation and diminishes the thymic cellularity (Fujikawa et al 2007;Peerzada et al 2013;Pozzesi et al 2014). Geldanamycin, a heat shock protein-90 inhibitor, which is usually used as an anti-cancer agent, can target several oncogenic signaling pathways simultaneously (Cortese et al 2013;Fukuyo et al 2010).…”

“…Geldanamycin, a heat shock protein-90 inhibitor, which is usually used as an anti-cancer agent, can target several oncogenic signaling pathways simultaneously (Cortese et al 2013;Fukuyo et al 2010). However, its administration along with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, may induce ATI through thymocyte death (Ohta et al 2007;Pozzesi et al 2014). Organotin compounds such as dibutyltin and tributyltin (TBTC) are recognized as environmental toxicants (Graceli et al 2013) that cause deterioration of the cell-mediated immunity through ATI (Pozzesi et al 2014;Tomiyama et al 2009).…”

“…However, its administration along with 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, may induce ATI through thymocyte death (Ohta et al 2007;Pozzesi et al 2014). Organotin compounds such as dibutyltin and tributyltin (TBTC) are recognized as environmental toxicants (Graceli et al 2013) that cause deterioration of the cell-mediated immunity through ATI (Pozzesi et al 2014;Tomiyama et al 2009). For instance, TBTC induces stress in the endoplasmic reticulum (Isomura et al 2013) and thereby causes the death of murine thymocytes (Sharma and Kumar 2014).…”

“…For instance, TBTC induces stress in the endoplasmic reticulum (Isomura et al 2013) and thereby causes the death of murine thymocytes (Sharma and Kumar 2014). The chemotherapeutic drug, 5-azacytidine has an anti-proliferative effect on T cell expansion (Fransolet et al 2016) and induces thymocyte death and ATI through a TNF-related apoptosis-inducing ligand-based mechanism (Pozzesi et al 2014;Tochitani et al 2011). It thus causes chemotherapy-mediated cytotoxicity and immuno-suppression in mice (Yu et al 2016).…”