Anti-inflammatory properties of bone morphogenetic protein 4 in human adipocytes.

BACKGROUND: Obesity is characterized by increased adipocyte number and size as well as white adipose tissue (WAT) inflammation, which is fundamental for the development of insulin resistance and type-2 diabetes. These processes, regulated by various endocrine, paracrine and autocrine factors, are extensively studied with the hope to interfere and to inhibit weight gain and related complications in obese patients. Recent data suggest an important role of bone morphogenic protein 4 (BMP4) in the regulation of adipogenesis and development of obesity. BMP4 is a growth factor of the transforming growth factor-ß superfamily. Initially, BMPs were identified as inducers of ectopic bone formation. It is now apparent, however, that these proteins have different pleiotropic developmental actions and including playing a role in white adipogenesis. METHODS AND RESULTS: Here, we demonstrate that the expression of BMP4 in human WAT is negatively correlated to body mass index and to the expression of pro-inflammatory cytokines. In vitro, BMP4 expression in cultured human adipocytes is upregulated after induction of differentiation. Cells treated with exogenous BMP4 increased peroxisome proliferator-activated receptor γ (PPARγ) expression and significantly reduced the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α) and monocyte chemoattractant protein 1. TNF-α treatment of fully differentiated adipocytes resulted in downregulation of the expression of adipogenic genes and elevated expression of pro-inflammatory cytokines. Exogenous BMP4 addition significantly reduced the negative effect of TNF-α on the expression profile of adipocytes. Finally, treatment of human adipocytes with exogenous BMP4 reduced the adipocytes' chemoattractant potential and the migration of monocytes toward adipocyte-conditioned medium. CONCLUSIONS: These results indicate that BMP4 is an important anti-inflammatory molecule, which may act through PPARγ and reduces TNF-α-mediated pro-inflammatory cytokine production in human adipocytes. Through its anti-inflammatory potential, BMP4 may serve as a protective factor for inflammation-related diseases such as insulin-tolerance or type-2 diabetes.

Leptin is essential in maintaining normal vascular compliance independent of body weight.

The adipocytokine leptin centrally regulates body weight by enhancing metabolic rate and signaling satiety, but it also has wide-ranging peripheral effects. Leptin receptors are expressed on vascular smooth muscle cells and have a role in maintaining vascular tone. We investigated the vascular effects of leptin repletion or calorie restriction on leptin-deficient mice (ob/ob) and a leptin antagonist on wild-type (WT) mice. Aortic compliance was assessed by the measurement of pulse wave velocity by noninvasive Doppler; blood pressure was measured by left ventricular catheterization. We found that ob/ob mice have much stiffer aortas than WT mice and that reduction in aortic stiffness was greater in ob/ob mice treated with leptin vs calorie restriction, despite similar weight loss. Interestingly, treating WT mice with a leptin antagonist increases aortic stiffness with no change in weight. Thus, we conclude that leptin is essential for maintaining normal aortic compliance independent of body weight.

Local humoral immunity in patients with pollen allergy.

All classes of immunoglobulins and albumin have been studied in different phases of disease, both in blood and in the nasal secretions of 75 patients with pollen allergy. There were 20 healthy persons in the test group. Total correlational analysis was done to determine interdependence of the researched indexes. The percentage of local synthesis of immunoglobulins in the nasal secretion was calculated with the help of Donovan's formula. The results obtained allowed us to find out that the local origin was responsible for 74% of total IgE, 97% of IgA and 10% of IgG in the nasal secretion in patients with pollen allergy. While comparing the results of skin tests with RAST, both in blood and in the nasal secretion, a positive coincidence was found considering the results of skin tests and RAST in serum in 93.8% cases, and in the nasal secretion in 91% of the cases. Coincidence between negative skin tests and the results of RAST in serum was as high as 89% of the cases. In some cases with negative skin test, specific IgE to the corresponding pollen allergens was found in the nasal secretion. In most of the cases there was correlation between allergen specific IgE in blood and in the nasal secretion in the phase of remission (88% of cases) and in the phase of exacerbation (100%). Total and allergen specific IgE in the nasal secretion can be widely used to diagnose allergy "in vitro".

Comparative estimation of general and local humoral immunity indicators in connection with local immunotherapeutic treatment.

All classes of immunoglobulins in blood and in the nasal secretions of 75 patients were studied in different phases of disease. There were 20 healthy persons in the control group. Forty patients were treated by preseasonal local immunotherapy through the application of water-salt extracts of pollen allergens intranasally, with the help of drops and aerosol during 2 years. It was found that the patients had a high level of total IgE in the nasal secretion, both in the phase of remission and especially in the phase of exacerbation, though the concentration of IgE in the nasal secretion, on the whole, was several times lower than in serum. Quantification of the level of IgE in the nasal secretion can be recommended to diagnosis allergy, "in vitro". The level of sIgA in the nasal secretion of the patients with pollen allergy was lower in comparison with the test group of healthy persons, being most remarkable in the phase of exacerbation. Patients with pollen allergy had a heightened level of IgD in blood with a marked reliability in the exacerbation phase. IgD was not detected in the nasal secretion. Local immunotherapy was found to have a high effectiveness of 80% after one course of treatment, and nearly 95% success with two courses. Therefore, we consider that local immunotherapy should be widely used. With the background of the local immunotherapy there were changes in the concentration of immunoglobulins, mainly in the nasal secretion of the immunoglobulins. IgE in the nasal secretion was lowered to a great extent after two courses of treatment. sIgA after local immunotherapy had a tendency to increase considerably after two courses of treatment. The increase of sIgA level and the lowering of IgE in the nasal secretion can be considered as immunologic criteria of local immunotherapy effectiveness.