Role of IL-6, sIL-6R, IL-1 beta, TNF-alpha, and B2M in pathophysiology and prognosis of multiple myeloma

Cytokines control myeloma cell proliferation, differentiation, apoptosis and tumor-induced bone marrow destruction. The present study was designed to estimate the serum levels of interleukin-6 [IL-6], soluble IL-6 receptor [sIL-6R], IL-1 beta, tumor necrosis factor-alpha [TNF-alpha], and beta-2 microglobulin [beta 2M] in multiple myeloma [MM] in an attempt to elucidate their role in the disease, to study their levels in different immunologic types of MM, and to evaluate the effect of therapy on these levels. The study included 40 patients with MM, 20 newly diagnosed [group I] and 20 patients receiving treatment [group II]. Ten patients received therapy for one year [group IIb]. Patients were subclassified according to beta 2M level into [patients with beta 2M < 6 mg/L and patients with beta 2M >/= 6 mg/L]. Fifteen healthy individuals were included as controls. Samples of all patients and controls were subjected to serum protein electrophoresis, immunofixation, serum cytokines [IL-6, IL-1 beta, TNF-alpha], sIL-6R, and beta 2-microglobulin estimation. Bone marrow aspiration [for patients only] and other laboratory chemical investigations were also performed. Serum immunofixation electrophoresis revealed that out of 40 patients, 25 were IgG myeloma, 12 were IgA myeloma, one case was light chain myeloma and 2 cases had biclonal gammopathy. Serum IL-6, sIL-6R, IL-1 beta, TNF-alpha and beta 2M showed significant increase in patient groups compared to controls, with no significant difference between groups I and II in both [IgG] and [IgA] myeloma. On the other hand, IL-6, sIL-6R, and beta 2M were significantly decreased in group IIb when compared with group I and group IIa. When beta 2M level was used for subgrouping, IL-6, sIL-6R, IL-1 beta, and TNF-alpha were significantly higher in group II patients with beta 2M >/= 6 mg/L than those with beta 2M < 6 mg/L. As IL-6, sIL-6R, IL-1 beta TNF-alpha, and beta 2M were elevated in all the studied myeloma patients, they might be involved in the pathophysiology of the disease irrespective of its immunologic type. IL-6 and sIL-6R could be used in monitoring the effect of therapy in MM especially in patients with impaired renal function. In addition of being known as a good prognostic marker, beta 2M could be used to monitor the response to therapy in MM

Leptin in obesity and type II diabetes mellitus: the merit of molecular methods in understanding pathogenesis

Leptin, the obese [OB] gene product, is a cytokine-like hormone that plays an important role in energy homeostasis. Mutation of OB in mice results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. This work was done to evaluate the importance of leptin in the pathogenesis of obesity, to study the relationship between serum leptin level and type II diabetes mellitus, and to compare molecular methods versus conventional serum leptin measurements in this respect. The study was done on 34 obese non diabetic patients, 61 non-insulin dependent diabetic patients [NIDDM], and 15 healthy volunteers as controls. Special investigations included serum leptin, insulin, C-peptide, cortisol, and growth hormone. Expression of leptin and leptin receptor were examined by RT-PCR in fat tissues of lipectomy samples from obese subjects. The results of this study revealed that there was significant elevation in leptin level in both obese and diabetic groups compared to controls. There was significant reduction in insulin levels in obese group compared to control group and a significant elevation in C-peptide level in diabetic non-obese group compared to control group. Serum leptin levels showed different patterns in cases of obesity ranging from low or normal to high leptin levels, which cannot by itself explain the cause of obesity. Leptin mRNA was expressed in 66.2% of cases and undetectable in 33.8% of cases. One sample showed longer than expected leptin amplicon. On the other hand, leptin receptor mRNA was detectable in 29.3% and undetectable in 70.7% of samples. This work shows that both NIDDM and obesity are two linked clinical situations in the sense that either of them seems to predispose to the other. Obese have significantly higher mean levels of serum glucose and lower levels of serum insulin and have tendency for developing diabetes. On the other hand, diabetics have higher BMI and have tendency for developing obesity. Serum leptin alone is not enough to explain the pathogenesis of obesity, but molecular methods for measuring both leptin and leptin receptor expressions might be important to explain the pathogenesis of obesity in some cases with hyperleptinemia

Hypermethylation of the PAX 5 gene promoter and its implication in the pathogenesis of multiple myeloma

This study aimed to clarify the mechanism of silencing of the PAX5 gene. The genetic analysis of the coding region and promoter by southern blot analysis did not show growth structural abnormalities in human multiple myeloma [MM] cell lines when compared with PAX5 expressing B cells. Several transcription factors like Ikaros-1 [IK-1] and SRY-related high mobility group [HMG] box [SOX4 and SOX5] showed a similar expression pattern in B cells and MM cells. Therefore, it was suggested that epigenetic factors could be involved in PAX5 silencing. The examination of the methylation pattern in PAX5 promoter revealed some areas of hypermethylation in methylation sensitive Southern blot analysis. Moreover, the treatment of MM cell lines by methylation blocking cytidine analogue 5-aza-2 deoxycytidine [5-aza-2dC] could restore the expression of PAX5 gene. It was postulated that hypermethylation of the PAX5 gene promoter may be responsible for its silencing in human MM. It was proposed that PAX5 gene silencing could be related to the oncogenesis of human MM