Doxycycline Protects Thymic Epithelial Cells from Mitomycin C-Mediated Apoptosis In Vitro via Trx2-NF-κB-Bcl-2/Bax Axis

Abstract

Background/Aims: Age-associated and stress-induced involution of the thymus is accompanied by reduced numbers of thymic epithelial cells (TECs) and severe reduction in peripheral T cell repertoire specificities. These events seriously affect immune function, but the mechanisms involved are unclear. Our preliminary findings showed that doxycycline (Dox) could drive the proliferation of a TEC line (MTEC1 cells) partially via the MAPK signaling pathway. Dox can also up-regulate IL-6 and GM-CSF expression via the NF-κB and MAPK/ERK pathways. Herein, we investigate the effects and mechanisms used by Dox that protect against mitomycin C (MMC)-induced MTEC1 cell apoptosis. Methods: MTEC1 cells were treated with Dox, MMC, and Dox plus MMC for different amounts of time. The expression of Trx2, NF-κB, Bcl-2, and Bax proteins were then detected by western blotting. Results: Our findings show that Dox protects MTEC1 cells from MMC-induced apoptosis. Dox up-regulated the expression of Trx2 and promoted NF-κB phosphorylation. Meanwhile, Dox also increased the expression of Bcl-2, partially reduced the expression of Bax, and normalized the ratio of Bcl-2 to Bax. Conclusion: Dox exerts an anti-apoptosis function via the NF-κB-Bcl-2/Bax and Trx2-ASK1/JNK pathways in vitro. Therefore, Dox may represent a drug that could be used to attenuate thymic senescence, rescue thymic function, and promote T cell reconstitution.

Thymic function in the regulation of T cells, and molecular mechanisms underlying the modulation of cytokines and stress signaling

“…Stress is able to disrupt homeostasis of the immune system, and various stressful conditions cause acute thymic involution, including emotional distress, malnutrition and pregnancy ( 56 , 57 ). Furthermore, numerous processes can trigger thymic involution during pathological conditions, such as bacterial and viral infections, inflammation, disease, clinical cancer treatment and preparative regimens for bone marrow transplants ( 58 ), as presented in Fig.…”

Acute Thymic Involution and Mechanisms for Recovery

“…Because ATI has been confirmed to be plastic in nature, it can be therapeutically reversed or halted (Wang et al 2016). Figure 5b illustrates the potential mechanisms underlying the therapeutic treatment of ATI in vitro (Wang et al 2016).…”

“…Other alterations include, but are not limited to, changes in the thymic epithelial cells (TECs), cortico-medullary ratio and apoptosis rates in the affected thymic tissues (Elmore 2006). Growing evidence suggests that ATI is plastic in nature and thus can be therapeutically reversed or halted (Wang et al 2016). For this reason, we also highlight recently discovered mechanistic and therapeutic tools (Table 1).…”

“…ATI is a common and well-known feature in various fungal Mendes-Giannini et al 2008;Souto et al 2003), viral (Duan et al 2015;Falkenberg et al 2014;Gao et al 2015) and bacterial infectious diseases (LeyvaRangel et al 2015;Ross et al 2012;Savino 2006). ATI can also be caused by immune suppression (Billard et al 2011;Zhou et al 2016), hunger (Gavia-García et al 2015;Savino et al 2007), chemotherapy, radiography (DeBo et al 2015;Lynch et al 2009), pregnancy (Ekin et al 2016;Jacques et al 2014Jacques et al , 2015, transplant rejection (Gracia-Ahufinger et al 2015;Krenzien et al 2015) and other severe disease conditions (Wang et al 2016). ATI in certain physiological conditions (e.g., during malnutrition and pregnancy) is usually mediated by the neuroendocrine system, and the transient thymic regression is characterized by increased thymocyte death, with the capability to recuperate after the removal of the insult (Gruver and Sempowski 2008;Shanley et al 2009).…”

Protective Effect of Genistein on Condylar Cartilage through Downregulating NF-κB Expression in Experimentally Created Osteoarthritis Rats

“…Many studies reported that IL-1β and TNF-α induced the nuclear translocation of NF-κB [10][11][12][13][14]. en, NF-κB activated the downstream Bcl-2 family proteins to regulate apoptosis [15,16]. Bcl-2 and Bax are both important members in the Bcl-2 family, which involved in the mechanism of apoptotic cell death [17].…”