Human cytomegalovirus induces caspase-dependent apoptosis of megakaryocytic CHRF-288-11 cells by activating the JNK pathway

Abstract

Human cytomegalovirus (HCMV) infection is usually implicated in thrombocytopenia occurring in newborns and immunocompromised patients. However, the underlying mechanisms remain elusive. This study was conducted to investigate the effects of HCMV infection on the viability of megakaryocytic CHRF-288-11 cells and the underlying mechanisms involved. RT-PCR for determining mRNA expression of HCMV immediate early gene 1 and Western blot for measuring protein expression of late HCMV gene pp65 showed that CHRF-288-11 cells were susceptible to HCMV infection. HCMV infection reduced the viability of CHRF-288-11 cells via apoptosis in a dose- and time-dependent manner. Both caspase 3 and c-Jun terminal kinase (JNK) signaling pathway were activated in the HCMV-treated CHRF-288-11 cells. z-DEVD-fmk (a caspase inhibitor) and SP600125 (a JNK inhibitor) significantly prevented the death of CHRF-288-11 cells induced by HCMV, respectively. Furthermore, inhibition of JNK activity could reduce the formation of active caspase 3 induced by HCMV. Interestingly, the co-application of antivirus drug ganciclovir and SP600125 synergistically prevented the death of CHRF-288-11 cells induced by HCMV. Collectively, these findings suggest that HCMV infection may induce the caspase-dependent apoptosis of megakaryocytic CHRF-288-11 cells by the activation of JNK signaling pathway.

Downregulated LRRK2 gene expression inhibits proliferation and migration while promoting the apoptosis of thyroid cancer cells by inhibiting activation of the JNK signaling pathway

“…The JNK signaling pathway is involved in cellular processes, including proliferation, differentiation and apoptosis, and is implicated in a number of diseases, including cancer, and neurological and immunological/inflammatory conditions (30). Activation of the JNK signaling pathway is involved in cell apoptosis due to numerous stimuli in cancer types, including breast and ovarian cancer (31,32). LRRK2 has been previously demonstrated to be able to act as a functional kinase mediating the autophosphorylation or phosphorylation of generic kinase substrates (33).…”

HCMV modulates c‐Mpl/IEX‐1 pathway‐mediated megakaryo/thrombopoiesis via PDGFRα and αvβ3 receptors after allo‐HSCT

“…In the present study, HCMV‐infected MKs exhibited a reduced c‐Mpl expression and higher serum TPO levels, which was in accordance with the increases in apoptosis and hypoploidy. Previous studies found that the TPO levels in plasma were mainly dependent on the rate of platelet production rather than the circulating platelet levels per se (Emmons et al, 1996). Ni and colleagues demonstrated that GPIbα‐deficient conditions could decrease hepatic TPO mRNA transcription and production (Xu et al, 2018), whereas increased cell surface expression of c‐Mpl served as a clearance sink for TPO in negative feedback (Murphy et al, 2013).…”

“…Although many studies have been performed in this field (Dou et al, 2010), most have focused on either observations or in vitro studies using HCMV strains. Little is known about the behavior of HCMV in patients after allo-HSCT, including whether HCMV directly targets MKs, how MK function changes after HCMV infection, whether MKs are permissive to HCMV infection, and what factors affect MK maturation and platelet generation.…”

The Role of Platelets in Viral Hemorrhagic Fevers

“…This is the case for some strains of Hantavirus associated with hemorrhagic fever, where megakaryocyte infection is thought to induce their destruction by T-cells [139]. Similarly, cytomegalovirus infection of megakaryocytes triggers caspase-mediated apoptosis resulting in thrombocytopenia [140]. Recent studies suggest that DENV also infects megakaryocytes, and inhibits megakaryopoiesis by inducing apoptosis in vitro [141,142].…”