Growth and survival of follicular and diffuse large B cell lymphoma cells: the role of toll-like receptors and their ligands, IL-21, BMP-4 and BMP-6
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The main purpose of this thesis was to characterize the expression of toll-like receptors (TLRs) and to investigate the role of TLR-induced responses in growth and survival of follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) cells. In addition, interleukin (IL)-21, bone morphogenetic protein (BMP)-4, and BMP-6 induced responses was explored in FL and DLBCL cells,. Lymphoma is a malignancy of lymphoid tissue and about 85% derive from B cells. B cells are involved in the host defense against infection by producing antibodies and are important for long-term immunological memory. Lymphoma can be divided into two main groups, Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL). While HL can be subdivided into two entities, there are currently over 50 entities of NHL and the most common type of NHL is DLBCL followed by FL. TLRs are essential in the host defense against infection and today 10 human TLRs have been characterized. B cells express several TLRs depending on maturation and stage of residence, and TLR- initiated responses in normal B cells include proliferation, anti-apoptotic effects and plasma cell (PC) differentiation. Chronic inflammation caused by persistent infection with a parasite, virus or bacterium is considered an important factor to tumor progression. Infections such as Helicobacter Pylori and Hepatitis C are commonly found in indolent lymphoma, and some of the patients respond with durable complete response after infection eradication. Previous studies have shown that malignant B cells respond to TLRs ligands with increasing survival and proliferation which may indicate that there are a link between cancer and inflammation. We found that TLR expression in the NHL primary cells mainly reflects the TLR expression in normal tonsillar B cells with the presence of TLR1, 2, 6, 7, and 9. The TLR expression was in agreement with their capacity to respond to incubation with TLR-specific ligands. TLR4 mRNA was expressed by NHL primary samples, NHL cell lines and one normal sample but in contrast to the normal B cells, increased proliferation was induced in NHL cells following stimulation with LPS. In addition, TLR3 expression and TLR3-induced responses were observed in two of the NHL cell lines. As in normal B cells, TLR-specific ligands FSL-1, Pam3Cys, R-848 and CpG OPN resulted in increased proliferation in most samples. NHL cells express IL-21R, although at various levels. The NHL patient cells responded to incubation with IL-21 with induced proliferation while NHL cell lines either responded with decreased proliferation or no response at all. Decreased proliferation was also observed in several NHL cells following stimulation with BMP-4 and BMP-6.In conclusion, TLR-specific ligands, IL-21, BMP-4, and BMP-6 may influence on growth and survival of FL and DLBCL.