Mumps Virus Can Suppress the Effective Augmentation of HPC‐Induced Apoptosis by IFN‐γ through Disruption of IFN Signaling in U937 Cells

Abstract

Cells of the human promonocytic cell line U937 were found to be sensitive to hexadeeylphosphocholine (HPC), which is a potential anticancer drug. Induction of apoptosis was found in U937 cells after treatment with HPC for 24 to 48 hr. The apoptosis in U937 cells exposed to HPC was increased significantly in the presence of interferon‐gamma (IFN‐γ). The augmentation of HPC‐induced apoptosis by IFN‐γ is repressed in cells (U937‐MP) persistently infected with mumps virus. A persistently infected cell line, U937‐MP, showed poor induction of signal transducers and activators of transcription‐1α (STAT‐1α), STAT‐2, p48 and IFN‐regulatory factor‐1 (IRF‐1), which are closely correlated with interferon‐α (IFN‐α) and IFN‐γ signaling pathways. Expression of MHC class‐I or class‐II was augmented by IFN‐α or IFN‐γ in U937 cells, but not in persistently infected cells. Therefore, it is suggested that the IFN‐γ signaling pathway plays an important role in the augmentation of HPC‐induced apoptosis. Mumps virus can suppress the IFN‐γ signaling pathway and subsequent development of apoptosis.

Function of Small Hydrophobic Proteins of Paramyxovirus

“…Since SV5 SH is not essential for SV5 growth in vitro and is involved in blocking apoptosis in infected cells, it is possible that MuV SH plays a similar role in blocking apoptosis in the mumps virus life cycle. This function of MuV SH is consistent with previous reports indicating that MuV is involved in blocking apoptosis in infected cells and that it may encode an antiapoptotic protein (13). Preventing infected cells from dying or from dying prematurely is beneficial to virus replication.…”

Induction of Apoptosis by Paramyxovirus Simian Virus 5 Lacking a Small Hydrophobic Gene

“…There are no obvious sequence homologies among SH proteins. Interestingly, both mumps virus and RS virus can block apoptosis, suggesting that they may also encode antiapoptosis proteins (22,30). Like SV5 without SH, a mutant mumps virus which has a defect in expressing SH protein grew normally in tissue culture cells, suggesting that the SH protein is not essential for mumps virus growth in tissue culture cells (47).…”

“…Some members of the Paramyxoviridae have also been found to inhibit apoptosis. For example, mumps virus can inhibit hexadecylphosphocholineinduced apoptosis of human promonocytic cells U937 (22). Respiratory syncytial (RS) virus inhibits TNF-␣-induced apoptosis in human respiratory epithelial cells and mononuclear cells (13,30).…”

Dysregulated Sonic hedgehog signaling and medulloblastoma consequent to IFN-α–stimulated STAT2-independent production of IFN-γ in the brain

“…Also, various agents are known to inhibit or deplete STAT2 and/or STAT1, possibly producing dysregulated IFN signaling and altered biological responses. These include (a) viruses that have the capacity to block the activation or induction of these STATs by IFNs (45)(46)(47); (b) physiological inhibitors of STATS, e.g., the suppressors of cytokine signaling (SOCS) (48); and (c) the recently identified germline mutations in human STAT1 that cause defective IFN signaling (49,50). This last point raises the possibility that mutations that similarly affect STAT2 might exist in the human population.…”