Vitamin D3 regulates LAMP3 expression in monocyte derived dendritic cells.

The family of lysosome-associated membrane proteins (LAMPs) encompassing LAMP1, LAMP2 and DC-LAMP (LAMP3) are the major constituents of the glycoconjugates coat present on the inside of the lysosomal membrane. LAMP3 is highly expressed only in certain cell types and during the differentiation stages. Its expression is linked the maturation of dendritic cells, inflammation, poor prognosis of certain tumors, and the locus where it is encoded was identified as a risk factor for Parkinson's disease (PD). Here, we investigated the capacity of Vitamin D3 to modulate the expression of LAMP3 during the dendritic cells differentiation and maturation. Our results demonstrated that the Vitamin D3 reduce the LAMP3 mRNA/protein expression during the dendritic cells differentiation and maturation, via NFκB pathways. Furthermore, we demonstrated that the Vitamin D3 was able to modulate the expression of LAMP3 likewise to in vitro tolerogenic dendritic cells. In summary, these data showed that the decrease of LAMP3 expression by Vitamin D3could enhance the tolerogenic characteristic of dendritic cells.

Interleukin-12 and tumour necrosis factor-alpha equilibrium is a prerequisite for clinical course free from late complications in children with type 1 diabetes mellitus.

The objective of the study was to analyse levels of IL-12 and TNF-alpha and relate the findings to the occurrence of microangiopathy in children with type 1 diabetes mellitus (DM). We examined a group of 123 children with type 1 DM. Serum levels of IL-12 and TNF-alpha were measured by an immunoenzymatic ELISA technique. TNF-alpha and IL-12 tended to be simultaneously present or absent in the sera of 50% of the children who had not developed complications, thus indicating a state of cytokine's equilibrium. Among the patients with an established retinopathy, two IL-12/TNF-alpha combinations were visible. Either a lack of detectable TNF-alpha was accompanied by measurable IL-12 serum concentrations or TNF-alpha incidence was associated with undetectable IL-12 values. Simultaneous lack of TNF-alpha and presence of IL-12 was associated with a better prognosis as these patients had a significantly lower albumin excretion rate. The state of equilibrium between TNF-alpha and IL-12 is beneficial in patients at early stages of the disease, prior to the occurrence of complications. Shifting the equilibrium towards TNF-alpha seems to promote late complications. It may suggest that a disharmony between pro- and anti-angiogenic function of these cytokines underlie the mechanism by which TNF-alpha and IL-12 shape the disease course.

High levels of circulating interleukin-10 in diabetic nephropathy patients.

AIMS: The aim of our study was to analyse the level of circulating interleukin-10 (IL-10) and relate it to the grade of albuminuria in patients with diabetic nephropathy (DN) due to type 1 diabetes mellitus (DM). Since IL-10 has met the criteria for an anti-inflammatory and an immunosuppressive cytokine, its activity may be important for clinical outcome of DN. METHODS: The IL-10 level was measured by ELISA in serum samples from thirty patients with DN due to type 1 DM, and compared with thirty patients with type 1 DM without DN and a control group of thirty, healthy, age- and sex-matched people. RESULTS: We observed a greatly elevated concentration of circulating IL-10 in 30/30 DM patients with DN (mean 140 pg/mL +/- 102), compared to DM patients without DN in whom IL-10 was detectable in only 11/30 patients (0.79 pg/mL +/- 1.24), and the group of healthy people in whom IL-10 was detectable in only 3/30 donors (0.92 pg/mL +/- 0.17). IL-10 appeared to be the strongest independent predictor of albuminuria, followed by HbA1c, diastolic blood pressure and DN duration. There was a positive correlation between the values of IL-10 and albuminuria in DM patients with DN. The patients in the fourth quartile of albuminuria had a distinctly higher concentration of IL-10 than those in the lower quartiles. CONCLUSIONS: The increased concentration of IL-10 in the serum samples from DM patients with DN seems to depend on the severity of the nephropathy. The excessive IL-10 production may indirectly contribute towards DN progression. On the other hand, it may explain the relatively long course of diabetic nephropathy.

Association between vascular endothelial growth factor and hypertension in children and adolescents type I diabetes mellitus.

The aim of the study was to analyse the relationship between the serum level of vascular endothelial growth factor (VEGF) and the incidence of hypertension (HT) in children and adolescents with type I diabetes mellitus (T1DM). One hundred and five patients with T1DM were enrolled in the study. The control group consisted of 30 healthy controls. All the T1DM patients were subjected to biochemical analyses, ophthalmologic examination and 24-h blood pressure monitoring. Besides, all the patients and healthy controls had serum VEGF levels measured with the use of the ELISA methodology. The essence of our research is that patients with T1DM and HT and with microalbuminuria (MA) and diabetic retinopathy (DR) (MA/DR) are characterized by a significantly higher level of VEGF (340.23±93.22 pg ml(-1)) in blood serum in comparison with the group of T1DM patients without HT and MA/DR (183.6±96.6 pg ml(-1)) and with healthy controls (145.32±75.58 pg ml(-1)). In addition, the VEGF level was significantly higher in T1DM patients, who presented all three complications, that is HT, retinopathy and MA in comparison with T1DM patients without HT, but with MA/DR (P=0.036). On the other hand, no statistically significant differences (P=0.19) were noted in the level of VEGF in serum between T1DM patients without HT and MA/DR and the healthy control group. At a further stage of analysis, using the method of multiple regression, it was shown that systolic pressure, HbA1c and duration of disease are independent factors influencing the concentration of VEGF. Summarizing, the measurement of VEGF serum levels allows for the identification of groups of patients who have the highest risk of HT and, subsequently, progression of vascular complications.

Overactivity of tumor necrosis factor-alpha but not interleukin 6 is associated with low natural killer cytotoxic activity in the elderly.

In this paper we asked whether the increased production of two proinflammatory cytokines-tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL6) in the absence of the inflammatory stimulus, a phenomenon frequently occurring in the elderly, may contribute to the decrease of natural killer (NK) cytotoxic activity. NK cell activity is a part of a nonspecific immunity directed against infected and transformed cells. We measured the levels of bioactive TNF alpha and IL6 during cytotoxic NK reactions and analyzed the effect of neutralizing monoclonal antibodies anti-TNF alpha and anti-IL6 on the outcome of cytotoxic reaction. Bioactive TNF alpha was produced in higher amounts during cytotoxic reactions of the elderly with low NK activity in comparison with its production by the elderly with high NK activity. Anti-TNF alpha decreased already low cytotoxic responses of the elderly while not having an effect on the cytotoxic potential of high responders. More of the bioactive IL6 was released during cytotoxic reactions of the elderly as compared with young people. There was, however, no relation between the height of NK cytotoxic activity and the amount of IL6. Our results suggest that the increased level of TNF alpha seen in the elderly low NK responders may pose a compensatory mechanism, necessary to keep the highest possible level of NK responses. The increased bioactivity of IL6 during NK reaction of the elderly does not seem to participate in the regulation of the level of NK cytotoxic activity.

Significance of tumor necrosis factor alpha in patients with long-standing type-I diabetes mellitus.

Fifteen out of the forty-five patients with long-standing diabetes mellitus type I were characterised by the presence of TNFalpha in the sera when examined on several occasions over a period of five years. TNFalpha-producing patients had a better control of the disease and a smaller percentage of them suffered from diabetic complications as compared with those not producing this cytokine. TNFalpha-producing patients had lower levels of the proinflammatory markers - IL6 and CRP, and higher concentrations of ACTH and cortisol than those not producing this cytokine. We suggest that TNFalpha released systemically in diabetic patients stimulates the hypophysis-adrenal axis, and in that way indirectly ameliorates autoimmune response occurring during the advanced phase of the disease.

Serum interleukin-6 levels and bone mineral density at the femoral neck in post-menopausal women with Type 1 diabetes.

BACKGROUND: Although osteopenia is often reported in Type 1 diabetes mellitus, the pathogenic mechanisms are not fully understood. Oestrogen deficiency also leads to decreased bone mineral density (BMD). Enhanced interleukin-6 (IL-6) production among Type 1 diabetic patients could be involved in the pathogenesis of diabetic bone loss since it is a potent bone resorbing cytokine. AIMS: To evaluate the relationship between serum bioactive IL-6 levels and BMD at the femoral neck of post-menopausal women with Type 1 diabetes. METHODS: We studied BMD, urine excretion of deoxypirydynoline crosslinks, serum bioactive IL-6 and soluble IL-6 receptor (sIL-6R) levels in 20 post-menopausal women with Type 1 diabetes mellitus, and compared these results with 20 matched healthy post-menopausal controls. RESULTS: Post-menopausal women with Type 1 diabetes had significantly lower BMD at the femoral neck and increased serum bioactive IL-6 levels compared with the control group, but no relationship was observed between these variables in a multiple regression analysis. Using BMD at the femoral neck of diabetic women as the dependent variable in the multiple step regression analysis model, we found that independent variables that were strongly associated with bone mass at the femoral neck in this group were: time since menopause and duration of diabetes. CONCLUSIONS: Although our study had a small sample size, we found that post-menopausal women with Type 1 diabetes mellitus present lower bone mass and higher serum bioactive IL-6 levels than matched healthy controls, but we were unable to find a correlation between these two parameters.