Assessment of proliferating cell nuclear antigen and its relationship with proinflammatory cytokines and parameters of disease activity in multiple myeloma patients

Abstract

Multiple myeloma (MM) is a malignant plasma cell disease. Several proinflammatory cytokines produced by malignant plasma cells and bone marrow (BM) stromal cells are involved in the pathogenesis of the disease. We evaluated serum levels of the proinflammatory cytokines Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), macrophage inflammatory protein-1α (MIP-1α), in MM patients before treatment, and determined its significance in tumor progression. We also analyzed the correlation between measured parameters with proliferating cell nuclear antigen (PCNA). Forty-four MM patients and 20 healthy controls were studied. Serum levels of the proinflammatory cytokines were measured using enzyme-linked immunosorbent assay (ELISA), whereas PCNA value in the BM was determined by immunohistochemistry staining. The mean concentrations of the measured cytokines were significantly different among the three stages of disease, with higher values in advanced disease stage. Furthermore, patients with MM had significantly higher serum levels of the measured cytokines than in controls. A positive correlation was found between IL-6 with IL-1β, IL-8 and MIP-1α. Similarly, IL-8 and MIP-1α were positively correlated with markers of disease activity such as β2 microglobulin and LDH. The proliferation index, determined by PCNA immunostaining, was higher in advanced disease stage. Furthermore PCNA value correlated significantly with β2 microglobulin, LDH and the levels of the measured cytokines. Our results showed that the proliferative activity, as measured with PCNA, increases in parallel with disease stage. The positive correlation between PCNA and other measured mediators supports the involvement of these factors in the biology of myeloma cell growth and can be used as markers of disease activity and as possible therapeutic targets.

Impaired Memory in OT-II Transgenic Mice Is Associated with Decreased Adult Hippocampal Neurogenesis Possibly Induced by Alteration in Th2 Cytokine Levels

“…NSCs with IL-4 showed significant decreased expression of PCNA than vehicle treated NSCs. The PCNA expression analysis data are in part consistent with a report that the level of IL-6, one of the Th2 cytokines, is correlated with PCNA levels in advancing disease stage ( Tsirakis et al, 2011 ). PCNA is a biomarker of NSC-specific cell proliferation as well as is needed to DNA replication in S-phase of adult hippocampal NSCs ( Arai et al, 2011 ; Mandyam et al, 2007 ; Paunesku et al, 2001 ).…”

Effects of IL-8 Up-Regulation on Cell Survival and Osteoclastogenesis in Multiple Myeloma

“…This is in fact indirectly suggested by the high content of IL-8 in the CM of BM cultures from myeloma patients ( Figure 1C), and also by the elevated serum levels of IL-8 found in MM patients. 58,59 In this study, we present evidence of osteoclastogenesis promotion by IL-8 from myeloma and stromal cultures and antiapoptotic effects of IL-8 on serum-deprived myeloma cells. These findings, together with the angiogenic and MM cell chemotactic roles of IL-8, 25,26 suggest that antieIL-8 therapy might be beneficial to prevent unwanted effects of IL-8 up-regulation because of interactions of myeloma cells with the microenvironment or treatment with antimyeloma drugs.…”

Ex-Vivo Dynamic 3-D Culture of Human Tissues in the RCCS™ Bioreactor Allows the Study of Multiple Myeloma Biology and Response to Therapy

“…To this aim, we first looked at β2 microglobulin concentration in culture supernatants from MM explants retrieved at different time intervals. Indeed, β2 microglobulin serum levels significantly correlate with PC proliferation index [32] and are commonly used for staging of MM. As shown in Figure 3A, β2 microglobulin was detectable in supernatants obtained after three days of culture; moreover, β2 microglobulin levels decreased in the presence of Bortezomib in all samples, but in patient 5, in accordance with the drug sensitivity of MM cells shown by morphological examination.…”