DUSP1 mediates BCG induced apoptosis and inflammatory response in THP-1 cells via MAPKs/NF-κB signaling pathway.

Tuberculosis (TB) is a zoonotic infectious disease caused by Mycobacterium tuberculosis (Mtb). Apoptosis and necrosis caused by the interaction between the host and the pathogen, as well as the host's inflammatory response, play an important role in the pathogenesis of TB. Dual-specificity phosphatase 1 (DUSP1) plays a vital role in regulating the host immune responses. However, the role of DUSP1 in the regulation of THP-1 macrophage apoptosis induced by attenuated Mycobacterium bovis Bacillus Calmette-Guérin (BCG) infection remains unclear. In the present study, we report that infection with BCG significantly induces macrophage apoptosis and induces the production of DUSP1, TNF-α and IL-1ß. DUSP1 knockdown significantly inhibited BCG-induced macrophage apoptosis and activation of MAPKs/NF-κB signaling pathway. In addition, DUSP1 knockdown suppressed BCG-induced inflammation in vivo. Taken together, this study demonstrates that DUSP1, as a regulator of MAPKs/NF-κB signaling pathway, plays a novel role in BCG-induced macrophage apoptosis and inflammatory response.

Knockdown of GBP1 inhibits BCG-induced apoptosis in macrophage RAW 264.7 cells via p38/JNK pathway.

Alveolar macrophage apoptosis induced by Mycobacterium tuberculosis (Mtb) plays a significant role in mediating the pathogenesis of tuberculosis. There is growing evidence that guanylate-binding proteins (GBPs) are associated with different pathological processes such as microbial infection. However, it remains unclear whether GBPs can regulate the apoptosis of macrophages induced by Mtb. In this study, we investigated the potential effect of GBP1 on RAW 264.7 cell apoptosis during Bacillus Calmette-Guerin (BCG) infection. The results demonstrated that BCG could induce macrophage apoptosis and GBP1 upregulation. In addition, we explored the role of GBP1 in regulating BCG-induced RAW 264.7 cell apoptosis using small interfering RNAs targeting GBP1. The results showed that knockdown of GBP1 could attenuate BCG-induced apoptosis in RAW 264.7 cells. Moreover, we found that GBP1 knockdown decreased the levels of cleaved-Caspase 3 and cleaved-PARP-1, while decreased those of cleaved-Caspase 9, BAX, Cytochrome C and APAF1. These findings imply that GBP1 knockdown can prevent BCG-induced apoptosis through an endogenous apoptosis pathway. In addition, the mitochondrial membrane potential of macrophages was significantly increased after BCG infection, and GBP1 knockdown could alleviate this phenomenon. Furthermore, downregulation of GBP1 also attenuated BCG-induced accumulation of reactive oxygen species in macrophages. Mechanistically, GBP1 suppressed the phosphorylation of the target molecules in p38/JNK pathway, thus regulating the apoptosis of BGC-infected macrophages. Collectively, these findings reveal a significant role of GBP1 in mediating cell apoptosis in macrophages infected with BCG, and the molecular mechanism underlying its suppressive effect on BCG-induced apoptosis.