Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma

Angiogenesis is a crucial process in growth and progression of cancer and there is growing evidence that neovascularisation is important in hematological malignancies. Since an increased angiogenic potential has been identified in multiple myeloma, we simultaneously measured circulating serum levels of the cytokines bFGF, VEGF, HGF and IL-6 by ELISA in 67 patients with multiple myeloma or monoclonal gammopathies of undetermined significance (MGUS) and in 20 controls. Median values of bFGF were 4.7 pg/ml in healthy volunteers, 6.2 in MGUS, 6.3 in myeloma stage I, 13.4 in stage II and 21.7 in stage III. Myeloma patients had significantly higher bFGF serum levels than controls (p<0.001). Pretreatment bFGF levels differed significantly in the Salmon and Durie stages I-III (p=0.02) and were significantly elevated in stage II-III compared to stage I myeloma (p=0.02). In patients responding to chemotherapy according to the CLMTF criteria, a significant decrease in serum bFGF, VEGF and HGF levels occurred (median pretreatment values for bFGF 23.9 pg/ml, post-treatment 6.5 pg/ml; p<0.001, for VEGF 223 pg/ml versus 105 pg/ml; p=0.02 and for HGF 1429 pg/ml versus 1077 pg/ml; p=0.02, respectively). In 11 patients who did not achieve a remission, there was no significant decrease in bFGF, VEGF and HGF levels. These data show that myeloma in stages II and III is associated with an increase in serum bFGF concentrations and give the first report that effective chemo-therapy is accompanied by a significant decrease in the angiogenic factors bFGF, VEGF and HGF, while no decrease of these factors could be found in nonresponders.     

Decreased ratio of circulatory vascular endothelial growth factor to endostatin in patients with systemic sclerosis--association with pulmonary involvement

OBJECTIVE: Vascular endothelial growth factor (VEGF) and endostatin appear to be involved in development of systemic sclerosis (SSc). We undertook this study to determine ratios of serum concentrations of VEGF to endostatin in SSc patients, healthy controls, assessments between cytokines, and lung-diffusing capacity (DLCO) as lung injury measurements related to interstitial lung disease (ILD). MATERIALS AND METHODS: Serum VEGF and endostatin levels were measured with ELISA in 28 SSc patients (16 with lcSSc) and 20-matched healthy volunteers, evaluating correlation and balance. DLCO was corrected for hemoglobin, alveolar volume, and determined with a single breath technique. RESULTS: SSc serum concentrations (median; range) of endostatin were higher than controls (107.2; 13.6-261.2 vs. 77.8; 18.0-110.4 ng/ml, p < 0.05); VEGF levels did not differ (151.2; 4.5-836.4 vs. 286.4; 23.7-708.5 pg/ml, p < 0.05). Ratios of VEGF to endostatin were 2.6 and 3.6 times lower (p < 0.05) in SSc and dcSSc in comparison to healthy subjects. There were significant negative correlations between VEGF, endostatin in SSc (r = -0.51), and controls (r = -0.57). SSc with ILD (n = 20) had similar concentrations of VEGF, endostatin, and ratios of VEGF to endostatin compared to SSc alone. No correlations were seen between DLCO, VEGF, endostatin and their ratios in the whole SSc group. Negative correlations were noted between DLCO and VEGF (r = -0.82), with DLCO and the ratio of VEGF to endostatin (-0.62) in lcSSc with ILD (n = 10). CONCLUSION: Decreased ratios of VEGF to endostatin may reflect imbalances between serum angiogenic, and anti-angiogenic activity in SSc, explaining impaired neoangiogenesis.     

流式微球阵列法检测烟雾病患者血清血管生成因子和炎性细胞因子水平

目的：检测烟雾病患者血清血管生成因子和炎性细胞因子水平,探讨其在烟雾病发病中的作用。方法利用流式细胞术微球阵列法检测56例烟雾病和26名健康对照者血清血管内皮生长因子（vascular endothelial grow th factor, VEGF ）、血管生成素－1（angiopoietin－1, Ang－1）、白细胞介素－8（interleukin－8, IL－8）、粒细胞集落刺激因子（granulocyte colony stimulating factor, G －CSF）、粒细胞－巨噬细胞集落刺激因子（granulocyte－macrophage colony stimulating factor, GM －CSF）和单核细胞趋化蛋白－1（ monocyte chemotactic protein 1, MCP－1）水平。结果烟雾病组血清 VEGF [（2.81±1.77）pg/ml 对（1.98±0.66）pg/ml; t =3.081, P =0.003]和 IL－8[（0.89±0.69）pg/ml 对（0.63±0.45）pg/ml;t'=2.0371,P <0.05]水平显著高于健康对照,而 Ang－1水平显著低于健康对照组[（830.01±289.29）pg/ml 对（961.65±232.87）pg/ml;t =－2.032,P =0.045]。结论烟雾病患者血清 VEGF、Ang－1和 IL－8水平与健康对照者存在显著差异,提示血管生成因子和炎性细胞因子可能在烟雾病发病中起着一定的作用。     

Cytokines are associated with postembolization fever and survival in hepatocellular carcinoma patients receiving transcatheter arterial chemoembolization

Objective

Cytokines play important roles in angiogenesis, inflammation, and cell growth. The present study aimed to investigate the correlation between cytokine changes and clinical characteristics in hepatocellular carcinoma (HCC) patients receiving transcatheter arterial chemoembolization (TACE).

Methods

Forty-one TACE-näive HCC patients receiving 73 sessions of TACE and 30 healthy controls were studied. Serum levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, epidermal growth factor (EGF), epidermal growth factor receptor, and transforming growth factor β1 (TGF-β1) before and at 1, 3, 5, 7, and 14 days after TACE as well as clinical parameters were analyzed.

Results

Baseline serum levels of VEGF, bFGF, IL-6, IL-8, and TNF-α in HCC patients were significantly elevated, whereas EGF and TGF-β1 levels were lower compared to those in healthy controls (p < 0.05 for all). Serum IL-6 increased rapidly and peaked on day 1 after TACE administration, whereas VEGF increased more slowly and peaked on day 14 after TACE administration. Patients with post-TACE fever had higher serum IL-6 levels on days 1, 3, and 5 (p < 0.005 for all). Patients with pre-TACE serum VEGF < 200 pg/ml had a longer survival than those with pre-TACE serum VEGF levels ≥ 200 pg/ml (22.2 months vs. 11.6 months, p = 0.014). Cox multivariate analysis showed that baseline serum VEGF significantly predicted survival for HCC patients receiving TACE.

Conclusions

TACE is associated with the modulation of serum angiogenic, inflammatory, and cell growth cytokines in HCC patients. Serum IL-6 correlates with post-TACE fever, and baseline serum VEGF independently predicts patient survival.     

Angiogenic factors may have a different prognostic role in adult acute lymphoblastic leukemia

Angiogenesis plays an important role in solid tumors and hematologic malignancies. The prognostic significance of angiogenic factors in adult acute lymphoblastic leukemia (ALL) remains ambiguous. We therefore analyzed the impact of angiogenic factor levels on overall survival of newly diagnosed adult ALL patients. Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin-1 receptor alpha (IL-1Ralpha), IL-6, IL-8, VEGF receptors VEGFR1 and VEGFR2, and thrombopoietin (TPO) were measured in plasma samples of 95 patients by enzyme-linked immunosorbent assay (ELISA). In a univariate Cox proportional hazards model, higher levels of IL-1Ralpha, IL-8, VEGFR1, and VEGFR2 were predictive of poor survival. In contrast, higher levels of VEGF were predictive of longer survival, and higher levels of bFGF suggested a similar trend (P = .09). The multivariate model simultaneously included VEGF (relative risk [RR] for death, 8.01; P = .001 for levels less than or equal to 19.5 pg/mL), IL-1Ralpha (RR, 5.12; P = .007 for levels greater than 373 pg/mL), and VEGFR2 (RR, 4.01; P = .04 for levels greater than 8222 pg/mL) as independent factors for survival. Of interest is the association of high levels of VEGF with good prognosis and higher levels of VEGF receptors with poor outcome. These data reflect the complexity by which angiogenic factors may affect the clinical behavior of patients with ALL, and this complexity should be considered in any therapeutic strategy incorporating antiangiogenic agents.     

Bcl-2 expression correlates positively with serum basic fibroblast growth factor (bFGF) and negatively with cellular vascular endothelial growth factor (VEGF) in patients with chronic lymphocytic leukaemia

A large proportion of B-chronic lymphocytic leukaemia (B-CLL) cells express the anti-apoptotic protein Bcl-2. Basic fibroblast growth factor (bFGF) has been shown to upregulate the expression of Bcl-2 in B-CLL cell lines. Vascular endothelial growth factor (VEGF) has been shown to enhance the survival of endothelial cells by upregulating the expression of Bcl-2. In the present study, we measured serum and cellular levels of bFGF and VEGF in 85 patients with CLL using a commercial quantitative sandwich enzyme immunoassay technique. Levels of Bcl-2 were also assayed concomitantly using Western blot analysis. The mean serum level of bFGF was 53.4 pg/ml (range 0-589) and that of VEGF 459.2 pg/ml (range 33-1793). The mean cellular level of bFGF was 158.3 pg/2 x 105 cells (range 0.8-841) and VEGF, 42.4 pg/2 x 105 cells (range 0-244). A high correlation was found between serum and cellular bFGF levels (P < 0.001), but not between the corresponding VEGF levels. Twenty-nine of 69 patients (42%) evaluated for Bcl-2 level, expressed it. The Bcl-2 level was positively correlated with the serum bFGF level (P = 0.007). However, surprisingly there was a negative correlation between Bcl-2 expression and intracellular VEGF level (P = 0.003). A positive correlation was also found between serum bFGF and disease follow-up time and log white blood cell count. These findings indicate that in CLL there is a correlation between angiogenesis-related factors and apoptosis-related protein expression, and elevated bFGF levels may account for the elevated Bcl-2 levels.     

羟氯喹抑制紫外线诱导的系统性红斑狼疮CD4+T细胞白细胞介素-10和干扰素-γ的表达

目的 研究紫外线对系统性红斑狼疮(SLE)CD4+T细胞因子的影响和羟氯喹的抑制作用.方法 选择SLE 30例,健康对照10名.磁珠分选SLE患者和健康人的CD4+T细胞,紫外线311 nm窄谱中波紫外线暴露,加入羟氯喹共培养,酶联免疫吸附试验(ELISA)检测培养上清白细胞介素(IL)-10和干扰素-γ的表达水平.采用t检验进行统计学分析.结果 SLE患者CD4+T细胞IL-10表达高于健康对照[(27±4)和(18±3) pg/ml,P=0.011];经45、100 mJ/cm2紫外线暴露后,SLE活动患者CD4+T细胞IL-10表达升高[(27±4)和(77±42) pg/ml,(40±18)和(77±42) pg/ml,P=0.022,P=0.048],经100 mJ/cm2紫外线暴露后,活动患者CD4+T细胞IL-10表达高于稳定患者[(77±42)和(24±4)pg/ml,P=0.029];羟氯喹降低SLE活动患者CD4+T细胞IL-10和干扰素-γ表达[(2.6±4.0)和(17.9±2.3)pg/ml,P=0.018,P=-0.017)];羟氯喹降低经45,100 mJ/cm2紫外线暴露后SLE活动患者T细胞IL-10表达[(40±18)和(22±6)pg/ml,(77±42)和(21±5) pg/ml,P=0.037,P=0.04];羟氯喹降低经100 mJ/cm2紫外线暴露的SLE活动和稳定患者T细胞干扰素-γ表达[(18±3)和(13±14) pg/ml,(19±7)和(12±5) pg/ml,P=0.013,P=0.049].结论 紫外线加重SLE患者体内Th1/Th2细胞因子的比例失衡;羟氯喹抑制了紫外线诱发SLE患者干扰素-γ和IL-10的表达.

Abstract：

Objective To explore the role of hydroxychloroquine (HCQ) in ultraviolet B (UVB)- induced expression of interleukin (IL)-10 and interferon (IFN)-γ from CD4+T cells in patients with systemic lupus erythematosus (SLE). Methods Thirty patients with SLE and 10 healthy controls were enrolled in the study. CD4+ T cells were isolated using magnetic beads from SLE patients and healthy controls. HCQ was added in culture media before and after irradiation with UVB 311 nm narrow band ultraviolet B (NB-UVB). The levels of IL-10 and IFN-γ in the supernatant were detected with enzyme-linked immunosorbent (ELISA). Comparisons between groups were performed by t-test. Results The level of IL-10 was higher in SLE patients [(27±4) pg/ml] than that in healthy controls [(18±3) pg/ml, P=0.011]. After exposure of CD4+T cells to UVB in 45 or 100 mJ/cm2 dosages, the level of IL-10 was increased significantly in patients with active disease (P=0.022, P=0.048). After exposure of CD4+T cells to UVB in 100 mJ/cm2 dosages, the levels of IL-10 was higher in patients with active disease [(77±42) pg/ml] than patients with stable disease [(24± 4) pg/ml, P=0.029]. When CD4+ T cell were cultured with HCQ, IL-10 and IFN-γ levels in patients with active disease [(2.6±4.0), (17.5±2.3) pg/ml] were decreased significantly (P=0.018, P=0.017). HCQ reversed UVB-induced IL-10 expression in active SLE patients after exposure of CD4+T cells to UVB in 45 or 100 mJ/cm2 dosages (P=0.037, P=0.04). HCQ also reversed UVB-induced IFN-7 expression in active SLE patients and stable SLE patients after exposure to CD4+T cells with UVB in 100 mJ/cm2 dosages (P=0.013, P= 0.049). Conclusion UVB can aggravate the imbalance of Th1 and Th2 cytokines. HCQ inhibits UVB-induced IL-10 and IFN-7 expression of CD4+T cells in patients with SLE, especially in patients with active disease.     

Vascular endothelial growth factor plasma levels in patients with systemic lupus erythematosus and primary antiphospholipid syndrome

The objective of this study was to assess the possible role of vascular endothelial growth factor (VEGF) in the pathogenesis of systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (PAPS). We studied 28 patients with SLE, 10 patients with PAPS, and 24 healthy controls. VEGF plasma levels were measured by ELISA. Immunolocalization of VEGF was done in renal tissue from SLE patients and cadaveric controls. Our results showed that VEGF plasma levels were increased in SLE patients compared with PAPS and controls. The correlation between clinical manifestations and VEGF levels revealed that SLE patients with renal failure had significantly increased plasma VEGF levels (134.1 + 91.0 pg/ml) compared with SLE patients with normal renal function (42.9 + 19.0 pg/ml), PAPS patients (41.9 + 26.6 pg/ml), and controls (36.2 + 27.0 pg/ml; P < 0.01). Immunostaining showed a strong expression of VEGF in SLE renal tissue samples. Our preliminary results indicate that VEGF is increased in plasma from patients with lupus nephritis and a moderate degree of renal failure and is overexpressed in renal tissue from these patients.     

Elevation of proinflammatory cytokine (IL-18, IL-17, IL-12) and Th2 cytokine (IL-4) concentrations in patients with systemic lupus erythematosus

Previous studies have indicated that the autoimmune phenomenon might be caused by an imbalance of T helper cell (Th) cytokines. We measured the plasma concentrations of three novel proinflammatory cytokines interleukin (IL)-17, IL-18, IL-12 and a key Th2 cytokine IL-4 in patients with systemic lupus erythematosus (SLE) and correlated the ratio of proinflammatory/Th2 cytokines with SLE disease activity index (SLEDAI). Plasma IL-12, IL-17, IL-18 and IL-4 concentrations of 36 SLE patients and 18 sex- and age-matched control subjects were measured by enzyme linked immunosorbent assay. All were significantly higher in SLE patients than control subjects (IL-12, mean+/-s.d. of 166.7+/-84.5 vs 93.5+/-39.2 pg/ml, P<0.001; IL-17, 76.5+/-45.7 vs 37.6+/-35.3 pg/ml, P=0.002; IL-18, 368.7+/-199. 5 vs 141.1+/-47.1 pg/ml, P<0.001; and IL-4, 27.1+/-15.3 vs 17.3+/-7. 2 pg/ml, P<0.05), and IL-18/IL-4 ratio correlated positively and significantly with SLEDAI score (r=0.435, P=0.006). We propose that SLE is characterized by an elevation of both Th1 and Th2 cytokines: the elevation of proinflammatory cytokine IL-12, IL-17 and IL-18 may trigger the inflammatory process in SLE and the elevation of IL-18/IL-4 ratio suggests an imbalance of cytokine profile to mediate the inflammatory response.     

Elevation of plasma interleukin-18 concentration is correlated with disease activity in systemic lupus erythematosus

BACKGROUND: Previous studies have indicated that the autoimmune phenomenon might be caused by an imbalance of T-helper cell (Th) cytokines. METHODS: We investigated the plasma concentrations of a novel pro-inflammatory Th1 cytokine, interleukin (IL)-18, and its inducer, IL-12, in patients with systemic lupus erythematosus (SLE) and correlated them with the SLE disease activity index (SLEDAI). Plasma IL-18 and IL-12 concentrations of 40 SLE patients and 18 sex- and age-matched control subjects were measured by enzyme-linked immunosorbent assay. RESULTS: Plasma IL-18 and IL-12 concentrations were significantly higher in SLE patients than in control subjects [median (interquartile range): IL-18, 320.0 pg/ml (164.4-475.6 pg/ml) vs 130.1 pg/ml (57.8-202.4 pg/ml), P<0.001; IL-12, 143.3 pg/ml (39.4-247.2 pg/ml) vs. 84.7 pg/ml (29.3-140.1 pg/ml), P<0.001]. Increases in IL-18 concentration correlated positively and significantly with SLEDAI score (r = 0.449, P = 0.004). CONCLUSION: The novel cytokine IL-18 might play a crucial role in triggering the inflammatory processes in SLE.     

Serum levels of vascular endothelial growth factor and basic fibroblast growth factor in patients with soft-tissue sarcoma

Purpose: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have been suggested to be important mediators for tumor-induced angiogenesis. We measured serum VEGF and bFGF levels from patients with soft-tissue sarcomas and correlated serum VEGF and bFGF levels with tumor status at surgery and histological grading. Materials and methods: A group of 18 healthy controls and 85 patients with soft-tissue sarcoma were enrolled in this study. The patients were classified according to tumor status at surgery. Serum levels of VEGF and bFGF were also correlated with histological grading. VEGF and bFGF levels were determined by enzyme-linked immunosorbent assay (Quantikine R&D Systems). Results: Serum VEGF and bFGF levels were significantly elevated in the patient group (VEGF: 580pg/ml, bFbF: 21pg/ml, P = 0.0001). The highest concentrations of serum VEGF and bFGF were found in patients with macroscopic tumor lesions or G3 histology. Serum VEGF levels showed a statistically significant correlation with tumor status and grading (P = 0.006 for tumor status, P = 0.0001 for grading). Conclusions: This study reveals that elevated preoperative serum VEGF and bFGF levels can be detected in the majority of patients with soft-tissue sarcoma. The significant correlation with tumor mass and histological grading suggests that a consecutive monitoring of VEGF and bFGF in the serum of patients with soft-tissue sarcoma might be a valuable marker for tumor follow-up. Received: 26 April 1999 / Accepted: 17 May 1999     

Concentrations of hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor in pericardial fluid and plasma

Some angiogenic factors, including hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF), have been reported to promote angiogenesis and improve myocardial perfusion in experimental models of ischemic heart disease. These factors are produced in various tissues, including myocardium. We measured the concentrations of HGF, bFGF, and VEGF by enzyme-linked immunosorbent assay in plasma and in pericardial fluid sampled during open heart surgery (12 patients with ischemic heart disease and 17 with nonischemic heart disease). HGF levels were significantly higher in plasma than in pericardial fluid (12.0 +/- 1.8 versus 0.26 +/- 0.04 ng/mL, P < 0.0001). On the other hand, bFGF levels were significantly higher in pericardial fluid than in plasma (243.5 +/- 50.9 versus 49.6 +/- 7.8 pg/mL, P = 0.009). VEGF levels were not significantly different between pericardial fluid and plasma (47.2 +/- 17.6 versus 24.5 +/- 3.6 pg/mL, P = 0.23). Concentrations of angiogenic factors in pericardial fluid and in plasma were not significantly different between patients with ischemic and nonischemic heart disease. These results suggest that the production, secretion, and kinetics of HGF, bFGF, and VEGF are different. These angiogenic factors may have different pathophysiologic roles.     

Increased concentration of proatherogenic inflammatory cytokines in systemic lupus erythematosus: relationship to cardiovascular risk factors

OBJECTIVE:. To examine the hypothesis that patients with systemic lupus erythematosus (SLE) have increased concentrations of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein-1 (MCP-1) and that these cytokines are associated with coronary risk factors and atherosclerosis. METHODS: Plasma IL-6, MCP-1, and serum IL-8 (pg/ml) concentrations were measured in 74 patients with SLE and in 85 controls. Clinical characteristics, homocysteine, lipids, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and coronary artery calcification as detected by electron beam computed tomography were measured. RESULTS: IL-6 (13.2 +/- 13.8 pg/ml vs 6.7 +/- 3.2 pg/ml, p < 0.001) and MCP-1 (264.2 +/- 581.8 pg/ml vs 131.0 +/- 63.7 pg/ml, p < 0.001) concentrations were higher in patients with lupus than in controls. IL-8 concentrations did not differ between patients and controls (p = 0.86). In patients, IL-6 concentrations were correlated with CRP (p < 0.001), ESR (p < 0.001), SLE disease activity index (SLEDAI, p = 0.003), and body mass index (BMI, p = 0.003). IL-6 concentrations were inversely correlated with HDL cholesterol (p = 0.01). MCP-1 concentrations were correlated with SLEDAI (p = 0.01), ESR (p = 0.04), and triglycerides (p = 0.03). After controlling for age, sex, disease activity, SLICC damage index, smoking status, and systolic blood pressure, IL-6 was associated with coronary calcification (odds ratio, OR = 1.07, p = 0.035). Similar models found no association between MCP-1 or IL-8 with coronary artery calcification. CONCLUSION: Patients with SLE have increased concentrations of IL-6 and MCP-1. These cytokines are associated with increased inflammation, BMI, and adverse lipid profiles. IL-6 is associated with burden of atherosclerosis in SLE.     

Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are elevated in peripheral blood plasma of patients with chronic lymphocytic leukemia and decrease after intensive fludarabine-based treatment

Chronic lymphocytic leukemia (CLL) is characterized by extraordinary heterogeneity in terms of clinical course with overall survival ranging from several months to dozens of years. It is currently not possible to accurately predict the future clinical course in an individual patient. Angiogenesis has been recently reported as a potential prognostic factor in various hematological malignancies including CLL. The objective of the present study was to quantify plasma levels of key angiogenic activators vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in patients with CLL and determine their potential change after intensive fludarabine-based treatment. Peripheral blood EDTA plasma concentrations of bFGF and VEGF were measured using comercially available enzyme-linked immunosorbent assay in 73 patients with untreated CLL (43 males, 30 females, median age, 65 years, range 31-88) and 80 healthy donors serving as control group. We found statistically significant increase in concentrations in patients with chronic lymphocytic leukemia compared to the control group (p < 0.0001 for both cytokines). No differences in angiogenic factors were noted between subgroups with low vs. intermediate vs. high-risk stage according to modified Rai staging or males vs. females. In twelve patients who achieved at least partial response after intensive fludarabine-based treatment, levels of bFGF as well as VEGF decreased significantly (bFGF, p = 0.0005; VEGF, p = 0.0068); in addition, they were no more significantly different from controls (bFGF, p = 0.524; VEGF, p = 0.728). Our data showed that key angiogenic activators bFGF and VEGF were elevated in plasma ofCLL patients. Furthemore, treatment with intensive fludarabine-containing regimens resulted in significant decrease of both cytokines. These data suggest that angiogenic cytokines may indeed play a significant role in CLL biology and that treatment with combination of fludarabine, cyclophosphamide +/- rituximab may exhibit antiangiogenic properties. Further studies with longer follow-up are necessary for evaluation of a possible association between angiogenic markers and progression-free survival or overall survival.     

Effect of rosuvastatin therapy and myocardial revascularization on angiogenesis in coronary artery disease patients

We studied the influence of rosuvastatin therapy and myocardial revascularization on angiogenic growth factors in coronary artery disease (CAD) patients. Two main groups were examined: the first one consisted of patients passed through successful percutaneous coronary intervention (PCI), the second one consisted of patients on 3 months rosuvastatin therapy. Vascular endothelial growth factor (VEGF), VEGF receptor Flt-1 (sVEGF-Rl) and transforming growth factor-beta (TGF-bl) levels were measured in healthy volunteers and CAD patients before and 6 days after myocardial revascularization by PCI. VEGF and basic fibroblast growth factor (bFGF) levels were measured before and 3 month after rosuvastatin therapy, as well as total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDLC), C-reactive protein (CRP), interleukin 6 (IL-6) and endothelium dependent vasodilation. VEGF levels did not differ, but TGF - b levels were significantly lower in CAD patients compared to healthy subjects (11.0 +/- 4.9 pg/ml and 120.0 +/- 32.4 pg/ml, respectively, p < 0.000l). Myocardial revascularization caused changes in VEGF levels from 192.4 +/- 166.1 pg/ml to 264.7 +/- 226.6 pg/ml (p=0.0066) without significant influence on TGF and VEGF-R1 levels in 6 days. There were positive changes in lipid levels, lowering of CRP and IL-6 concentrations, improvement of endothelial function and decrease of VEGF levels from 382 +/- 249 pg/ml to 297 +/- 220 pg/ml (p=0.006) 3 month after start of rosuvastatin treatment (no changes in bFGF levels were observed). Chronic insufficient myocardial blood supply leads to decreasing of TGF - b levels. The elevation of VEGF after myocardial revascularization reflects transient ischemia and potentially may provoke hemodynamic instability, caused by atherosclerotic plaque neovascularization. Strengthening of statin therapy early after myocardial revascularization may allow to stabilize the atherosclerotic plaque condition, also by means of VEGF lowering.     

Increased production of vascular endothelial growth factor by peripheral blood mononuclear cells in patients with inflammatory bowel disease

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic, vascular permeability-enhancing cytokine with overexpression in various pathological disorders, including tumour growth, chronic inflammation and tissue repair. Recent studies have shown significantly increased serum levels of VEGF in patients with inflammatory bowel disease. The origin of the circulating VEGF is still unknown. The present investigation examines the VEGF production by peripheral blood mononuclear cells (PBMCs) in patients with inflammatory bowel disease. METHODS: VEGF levels were measured in culture supernatants of unstimulated PBMCs of 27 patients with inflammatory bowel disease and 10 healthy volunteers using a solid phase ELISA. In addition, VEGF serum levels were determined. RESULTS: PBMCs of both active Crohn's disease patients (1142.6+/-483.9 pg/ml, P < 0.001, n = 12) and active ulcerative colitis patients (748.0+/-637.6 pg/ml, P = 0.006, n = 4) produced significantly higher amounts of VEGF compared with PBMCs of healthy volunteers (113.4+/-101.8 pg/ml, n = 10). In addition, there was a significantly increased VEGF production by PBMCs of patients with active disease compared with PBMCs of patients with quiescent Crohn's disease (261.6+/-254.8 pg/ml, P < 0.001, n = 7) and inactive ulcerative colitis (147.7+/-100.3 pg/ml, P = 0.02, n = 4). There was no significant difference in VEGF release between patients with inactive inflammatory bowel disease and healthy controls. CONCLUSIONS: Significantly increased VEGF production by PBMCs was found in patients with active Crohn's disease and active ulcerative colitis. The study helps to clarify one of the origins of the significantly enhanced VEGF serum levels in patients with active inflammatory bowel disease observed in recent studies.     

Clinical significance of interleukin-36 alpha and gamma in systemic lupus erythematosus patients: Potential relation to disease activity and subclinical arthritis

Aim of the workTo assess serum of interleukin-36 alpha (IL-36α) and interleukin-36 gamma (IL-36γ) levels in systemic lupus erythematosus (SLE) patients and to explore their association with clinical and laboratory features of SLE and with ultrasound evidence of subclinical hand arthritis.Patients and methodsThe study included 84 SLE patients without overt arthritis and 84 matched controls. The serum levels of IL-36α and IL-36γ were measured and compared between patients and controls. The hands and wrists of all patients underwent musculoskeletal ultrasound evaluation for evidence of subclinical arthritis and tenosynovitis. The SLE disease activity score was assessed for all patients.ResultsThe mean of serum IL-36α (65.5 ± 38.9 pg/ml) and IL-36γ (468.9 ± 315.9 pg/ml) were significantly higher in SLE patients compared to controls (37.9 ± 17.2 pg/ml and 151.1 ± 73.4 pg/ml; p < 0.001 each). IL-36α and IL-36γ had the ability to discriminate between SLE patients and controls with an AUC of 0.69 and 0.83 respectively. Serum IL-36α was significantly correlated with SLEDAI score (p = 0.04), synovitis (p < 0.001),Us erosion score (p = 0.01) and PD signals score (p = 0.002). Serum IL-36γ was significantly correlated with serum creatinine level (p = 0.04). SLE patients with arthralgia had significantly higher IL-36α serum level than patients without (p = 0.04). SLE patients with proteinuria had significantly higher IL-36γ than those without (p = 0.04). The linear regression analysis model revealed that the US evidence of synovitis was the strongest factor associated with the serum level of IL-36α meanwhile proteinuria was the strongest factor associated with the serum level of IL-36γ.ConclusionIL-36αserum level was significantly associated with SLEDAI score, arthralgia and US evidence of subclinical arthritis. IL-36γ serum level was significantly associated with proteinuria.     

Increased serum levels of interleukin-15 in rheumatoid arthritis with long- term disease

OBJECTIVE: To study the serum levels of IL-15 in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), seronegative spondyloarthropathies (SSd) and healthy donors. METHODS: The IL-15 serum levels were measured by ELISA in sera from 50 RA patients, 30 patients with SLE, 30 patients with SSd and 30 healthy donors. In RA patients, several clinical and demographic parameters were also obtained at the time of sample collection. IL-15 levels were compared in different RA subpopulations (positive or negative rheumatoid factor [RF], long term or recent onset disease, high or low disease activity). In addition, the possible association with other demographic and clinical parameters (gender, age, disease duration, etc) was also analysed. RESULTS: RA patients had significantly higher serum levels of IL-15 (102.4 +/- 150 pg/ml; p = 0.0001) than SLE patients (9.8 +/- 15.3 pg/ml), SSd patients (7.9 +/- 14.6 pg/ml) and healthy donors' (5.2 +/- 11.6 pg/ml). RA patients with a disease evolution less than 2 years showed lower IL-15 levels (33.7 +/- 62.2 pg/ml) than those with long-term disease (152.4 +/- 64.6 pg/ml; p = 0.004). In addition, a significant correlation between IL15 in serum and the number of disease-modifying antirheumatic drugs (DMARDs) prescribed was detected in RA patients (r = 0.42; p = 0.002). No association between IL-15 levels and age, gender, RF or disease activity was observed in this group. CONCLUSION: IL-15 is elevated in RA patients, specially in those with long term disease, compared to other rheumatic disorders. This finding supports that IL-15 is involved in the perpetuation of RA synovitis.     

Correlation between serum concentrations of soluble Fas (CD95/Apo-1) and IL-18 in patients with systemic lupus erythematosus

Recent researches suggest that imbalance in apoptotic process may lead to susceptibility to systemic lupus erythematosus (SLE). Production of pro-inflammatory cytokines, such as IL-18, has important role in autoimmune process in lupus. There are cumulative data on the pro-apoptotic role of IL-18, in the Fas-mediated apoptosis. Soluble Fas (Apo/1-CD95) is a marker of apoptosis that appears to increase in serum of SLE patients. Previous studies demonstrated increasing serum concentrations of soluble Fas (sFas) and IL-18 in SLE. To assess the correlation between serum concentrations of sFas and IL-18 in SLE patients, 114 SLE patients were selected randomly at the different stages of disease activity according to SLEDAI2K. IL-18 and sFas serum concentrations were compared in patients and fifty randomly selected healthy volunteers. The correlations of IL-18 and sFas serum concentrations with SLEDAI2K and with each other were evaluated in patients. There were a significant difference between serum concentrations of sFas and IL-18 in the case and control groups (P = 0.001). There was a significant correlation between serum concentrations of sFAS and IL-18 in SLE patients (P < 0.0001, r = 0.411). The elevations of IL-18 and sFas(Apo/1-CD95) serum concentrations in SLE patients are significantly correlated.     

Serum IL-6 and IL-12 levels in breast cancer patients

Previous studies indicated that interleukins 6 & 12 are multifunctional cytokines which regulate of immune response and cancer cell proliferation. We measured serum levels of these cytokines in 40 females with breast cancer and examined their correlation with clinicopathological variables including stages of the disease and estrogen and progesterone receptor expression on tumor cells. Serum levels of IL-6 (mean =111.38 pg/ml) as well as IL-12 (mean=1142.75 pg/ml) were significantly increased in breast cancer patients as compared to controls (mean 1.75 pg/ml &19.90 pg/ml respectively). A statistically significant correlation was found between levels of IL-6 as well as IL-12 and progression of the tumor (P < 0.05). However, no statistical difference was found in serum levels of these cytokines between metastatic and non-metastatic cases. Both cytokines negatively correlated with estrogen and progesterone receptor expression on tumor cells. In conclusion, serum levels of IL-6 and IL-12 are highly elevated in breast cancer patients and correlate with tumor progression. Assays for serum levels of IL-6 and IL-12 can be used as predictive non-invasive tests for tumor progression in breast cancer patients.