Consecutive stimulation of HBsAg promotes the viability of the human B lymphoblastoid cell line IM-9 through regulating the SIRT1-NF-κB pathway

Abstract

Abstract.Patients with chronic HBV infection have been reported to suffer a significantly increased risk of NHL, but the underlying mechanisms remain to be clearly explained. The aim of the present study was to clarify the relationship between chronic HBV infection and NHL development. Fluorescence-activated cell sorting, Annexin V/7-aminoactinomycin D staining and MTS assay were used to analyze the rate of apoptosis and cell viability. In addition, western blotting was used to detect protein expression. The effects of the activator of SIRT1, SRT1720, and the inhibitor of SIRT1, nicotinamide, were also analyzed. The expression levels cytokines and chemokines were determined by multiplex assay. Hepatitis B surface antigen (HBsAg) was demonstrated to increase the viability of the human peripheral B lymphoblastoid cell line, IM-9, in a dose-and time-dependent manner. HBsAg also decreased histone H3 acetylation and p21 expression at the molecular level. HBsAg upregulated the expression of anti-apoptotic B-cell lymphoma-extra-large and B-cell lymphoma 2 proteins, and inactivated the intrinsic apoptosis pathway by reducing BCL2 associated X, apoptosis regulator expression and increasing the expression of sirtuin 1 (SIRT1) and nuclear factor-κB (NF-κB). HBsAg also altered the levels of certain chemokines and cytokines, including interleukin (IL)-4, -10 and -12, C-X-C motif chemokine 10 and C-C motif chemokine ligand 5. Inhibition of SIRT1 suppressed the effects induced by HBsAg. The anti-apoptotic effect of HBsAg in IM-9 cell lines occurred via the promotion of cell viability, inhibition of apoptosis, regulation of chemokines and cytokines, acetylation of histone H3 and alteration of SIRT1 and NF-κB expression. In conclusion, chronic stimulation with HBsAg promoted the viability of the human B lymphoblastoid cell line, IM-9, through regulation of the SIRT1-NF-κB pathway. This may be an underlying mechanism of HBV-associated NHL.

Establishment and characterization of HBV-associated B lymphocytes with an immortalization potential

“…The possible mechanism of these cells development may be that chronic antigenic stimulation might cause sustained activation and proliferation of B-cells, predisposing to DNA damage, cytogenetic aberrations, overexpression of proto-oncogenes and transformation into SIBC. JIAN BO and coworkers demonstrated that HBsAg was able to promote cell viability and to reduce apoptosis in the human peripheral lymphoblastoid cell line, IM-9 through the SIRT1‑NF‑κB signaling pathway [38]. Another research found that CDR3 sequences of Ig exhibited a significant homology to HBsAb in HBsAg positive DLBCL, suggesting that HBV-associated DLBCL might originate from HBV antigen-selected B cells [39].…”

Primary hepatic mucosa-associated lymphoid tissue lymphoma with HP and previous HBV infection: A case report and literature review

“…HBV is hepatotrophic and lymphotrophic. Bo et al [12] co-cultured HBsAg with the human lymphoblastoid cell line IM-9 in vitro and found that chronic HBsAg stimulation could promote the viability of IM-9 cells by regulating the sirtuin 1(SIRT1)-nuclear factor-κB(NF-κB) pathway, finally resulting in the formation of HBV-associated NHL. In a clinical study involving 313 Chinese patients with NHL [13], the HBsAg positivity rate was 12.7%, which was higher than that of the general population (7.2%).…”

Hepatitis B virus infection status is not associated with poor prognosis in classical Hodgkin lymphoma patients

“…Hepatitis B virus (HBV), a hepatotropic virus, can also infect peripheral blood mononuclear cells and lymph nodes [1]. HBV infection has been found to play a causative role in lymphomagenesis by either chronic antigenic simulation model [2] or antigen-independent mechanism [3]. An epidemiological study involving 603,585 participants showed that hepatitis B surface antigen (HBsAg)-positive participants had an increased risk of non-Hodgkin lymphoma (NHL) overall compared with those who were HBsAg-negative (hazard ratio = 1.74).…”