Biomedical subjects

Alberto Sulli

Publications and source records attributed to Alberto Sulli.

14 recordsLinked to original sources

PubMed2005

Sex hormone modulation of cell growth and apoptosis of the human monocytic/macrophage cell line.

Sex hormones seem to modulate the immune/inflammatory responses by different mechanisms in female and male rheumatoid arthritis patients. The effects of 17beta-oestradiol and of testosterone were tested on the cultured human monocytic/macrophage cell line (THP-1) activated with IFN-gamma in order to investigate their role in cell proliferation and apoptosis. Activated human THP-1 cells were cultured in the presence of 17beta-oestradiol and testosterone (final concentration, 10 nM). The evaluation of markers of cell proliferation included the NF-kappaB DNA-binding assay, the NF-kappaB inhibition complex, the proliferating cell nuclear antigen expression and the methyl-tetrazolium salt test. Apoptosis was detected by the annexin V-propidium assay and by the cleaved poly-ADP ribose polymerase expression. Specific methods included flow analysis cytometry scatter analysis, immunocytochemistry and western blot analysis. Cell growth inhibition and increased apoptosis were observed in testosterone-treated THP-1 cells. Increased poly-ADP ribose polymerase-cleaved expression and decreased proliferating cell nuclear antigen expression, as well as an increase of IkappaB-alpha and a decrease of the IkappaB-alpha phosphorylated form (ser 32), were found in testosterone-treated THP-1 cells. However, the NF-kappaB DNA binding was found increased in 17beta-oestradiol-treated THP-1 cells. The treatment with staurosporine (enhancer of apoptosis) induced decreased NF-kappaB DNA binding in all conditions, but particularly in testosterone-treated THP-1 cells. Treatment of THP-1 by sex hormones was found to influence cell proliferation and apoptosis. Androgens were found to increase the apoptosis, and oestrogens showed a protective trend on cell death--both acting as modulators of the NF-kappaB complex.

Apoptosis↗

PubMed2005

Capillaroscopy.

Raynaud's phenomenon (RP) is the most common and significant clinical condition with an indication for a microvascular analysis to be carried out as soon as possible. Microvascular involvement is a key feature of RP and several rheumatic diseases are characterised by the presence of RP. Nailfold capillary microscopy shows an impressive cost/effectiveness ratio: it is simple, non-invasive and inexpensive. Well recognised nailfold videocapillaroscopic patterns (NVC) have been described mainly in systemic sclerosis (SSc) patients with secondary RP. The peripheral microvascular damage in SSc is characterised by increasing structural alterations of the capillaries (giant capillaries and microhaemorrhagies) with a progressive decrease in their density. The detection of the scleroderma NVC pattern allows an early distinction between the primary RP (functional, not disease associated) and the secondary RP (disease associated). Other major NVC patterns have been described in the field of rheumatic diseases. Interestingly, correlations are evident between the NVC and the clinical symptoms, severity of the disease and the laboratory findings.

Clinical Trials as Topic↗

PubMed2005

Nocturnal hormones and clinical rhythms in rheumatoid arthritis.

It is well known that some clinical signs and symptoms of rheumatoid arthritis (RA) vary within a day and between days; the morning stiffness that is observed in patients who have RA has become one of the diagnostic criteria of the disease. The circadian changes in the metabolism or nocturnal secretion of endogenous corticosteroids is certainly responsible, in part, for the time-dependent changes that are observed in the inflammatory response and related clinical symptoms. More recently, melatonin (mLT), another circadian nocturnal hormone that is the secretory product of the pineal gland, has been implicated in time-dependent inflammatory reactions, with effects that are opposite of those of corticosteroids. Therefore, altered functioning of the hypothalamic-pituitary-adrenocortical axis (reduced corticosteroid production) and of the pineal gland (increased mLT production) found in RA patients seem to be important factors in the perpetuation and clinical circadian symptoms of the disease. Consistently, human proinflammatory Th1-type cytokine production (related to mLT stimulation) exhibits a diurnal rhythmicity, with peak levels during the night and early morning, at a time when plasma cortisol (inducing Th2-type cytokine production) is lowest and mLT is highest. Reduced daily light exposure as observed in northern Europe (Estonia), at least during the winter, might explain the higher and more prolonged mLT concentrations as well as some epidemiological features that are observed in northern European patients with RA versus southern European patients.

Arthritis, Rheumatoid↗

PubMed2004

Pregnancy, cytokines, and disease activity in systemic lupus erythematosus.

OBJECTIVE: To evaluate levels of selected cytokines and soluble receptors involved in the humoral immune response during pregnancy in systemic lupus erythematosus (SLE) patients. METHODS: Seventeen consecutive SLE patients and 8 matched healthy controls were prospectively studied during pregnancy. Sera were obtained within the last 3 months prior to pregnancy; at 9, 17, and 29 weeks of pregnancy; and at 1 month after delivery. Serum levels of interleukin-10 (IL-10), interleukin-6 (IL-6), and soluble tumor necrosis factor receptors p55 (sTNFR I) and p75 (sTNFR II) were evaluated. SLE activity was measured by the European Consensus Lupus Activity Measurement score modified for pregnancy. RESULTS: IL-10 serum levels were found to be higher (P <0.0001) in patients than in controls before conception, and still higher (P <0.0001) in SLE patients during gestation, without intertrimester changes. In SLE patients, IL-6 serum levels did not increase in the third trimester of pregnancy, as was observed in controls (P=0.011). No significant differences between SLE patients and controls were found in either sTNFR I or II levels or profiles before and during pregnancy. IL-10 and sTNFR I levels were significantly higher during pregnancy and postpartum in SLE patients with active disease (P=0.03 and P=0.01, respectively). CONCLUSION: The levels of some cytokines involved in the humoral immune response seem to be modified in the peripheral circulation of pregnant SLE patients. The most relevant modifications are the lower than expected increase of IL-6 in the third trimester of gestation and persistently high levels of IL-10 during pregnancy.

Adult↗

PubMed2004

Synovial fluid estrogens in rheumatoid arthritis.

Experimental and clinical evidence suggest that immune reactivity is modulated by gender. Immune reactivity is greater in females than in males and lymphocytes and monocytes from female subjects shows higher antigen presenting activity and mitogenic responses. Steroid hormones can be converted along defined pathways to downstream hormones in the periphery. The conversion of dehydroepiandrosterone (DHEA) in target macrophages leads to an increase of downstream effector hormones (including estrogens), which may be an important factor for local immunomodulation at least in RA synovitis. The presence in the RA synovial fluids (SF) of an altered sex hormone balance resulting in lower immunosuppressive androgens and higher immunoenhancing estrogens, might determine a favorable condition for the development of the immuno-mediated RA synovitis and synovial hyperplasia. The increased estrogen concentration observed in RA SF of both sexes are characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, that is a mitogenic and proliferative endogenous hormone. In contrast to 16alpha-hydroxylated estrogens, the 2-hydroxylated forms inhibit growth promoting effects of E2 and were found low in RA SF. Therefore, dose-related conversion to pro- or anti-inflammatory downstream metabolites of estrogens might support the dual role of estrogens (pro or anti-inflammatory) for example during estrogen replacement therapy, depending on local concentration (i.e. SF in RA) of 16alpha-hydroxyestrone or 2-hydroxyestrogens.

Arthritis, Rheumatoid↗

PubMed2002

Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus.

OBJECTIVES: To analyze the variation of steroid hormone levels during pregnancy in patients with systemic lupus erythematosus (SLE). Moreover, to investigate whether, during gestation, there is any relationship between steroid concentration and SLE activity. METHODS: Seventeen consecutive pregnant SLE patients and 8 matched healthy pregnant controls were studied prospectively. Disease activity was evaluated by European Consensus Lupus Activity Measure (ECLAM) score modified for pregnancy. The following hormones were evaluated: testosterone, 17beta-estradiol (estradiol), cortisol, dehydroepiandrosterone sulfate (DHEAS), and progesterone. RESULTS: Disease activity score significantly varied during pregnancy and postpartum (P< 0.05), being decreased in the third trimester and increased in the second trimester and postpartum. Serum levels of all steroids varied significantly during pregnancy and the postpartum period both in patients and in healthy subjects. In SLE patients, estradiol, progesterone, and DHEAS concentrations were found to be significantly reduced compared with controls. Serum level profiles of estradiol and progesterone were different from those observed in controls. No differences in the steroid levels were observed between patients taking prednisone 5 mg/day, apart from cortisol, which was, as expected, lower in the latter group. CONCLUSIONS: The major hormonal alteration observed during pregnancy in SLE patients was an unexpected lack of estrogen serum level increase, and, to a lesser extent, progesterone serum level increase, during the second and-even more-the third trimester of gestation. This lack of increase probably was due to placental compromise. Therefore, these steroid hormone variations may result in a lower humoral immune response activation, probably related to a change in the estrogen/androgen balance, that in turn could account for the decrease in disease activity observed during the third trimester in pregnant SLE patients.

Adult↗

PubMed2002

Sex hormones and rheumatoid arthritis.

Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immune-suppressors. In male rheumatoid arthritis (RA) patients, androgen replacement seems to ameliorate the disease and supports their involvement in the pathophysiology of the disease. The combination of androgens with cyclosporin A or methotrexate has been found to potentiate the apoptosis of monocytic inflammatory cells as well as to reduce the cell growth at least in vitro. Considerable interest has been devoted in the last years as to whether the use of oral contraceptive pills (OCs) may have a protective effect on the risk of RA. The results of many controlled studies have been found contradictory. At the present time, no consensus has been achieved regarding OCs administration and its relationship to the prevention or development of RA. In addition, an association of estrogen receptor gene polymorphism with age at onset of RA has been observed and might further explain inter-individual clinical and therapeutical-response variations. Local increased estrogen concentrations and decreased androgen levels have been observed in RA synovial fluids and seem to play a more important role in the immune/inflammatory local response.

Androgens↗

PubMed2002

Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis.

Generally, androgens exert suppressive effects on both humoral and cellular immune responses and seem to represent natural anti-inflammatory hormones; in contrast, estrogens exert immunoenhancing activities, at least on humoral immune response. Low levels of gonadal androgens (testosterone/dihydrotestosterone) and adrenal androgens (dehydroepiandrosterone and its sulfate), as well as lower androgen/estrogen ratios, have been detected in body fluids (that is, blood, synovial fluid, smears, salivary) of both male and female rheumatoid arthritis patients, supporting the possibility of a pathogenic role for the decreased levels of the immune-suppressive androgens. Several physiological, pathological, and therapeutic conditions may change the sex hormone milieu and/or peripheral conversion, including the menstrual cycle, pregnancy, the postpartum period, menopause, chronic stress, and inflammatory cytokines, as well as use of corticosteroids, oral contraceptives, and steroid hormonal replacements, inducing altered androgen/estrogen ratios and related effects. Therefore, sex hormone balance is still a crucial factor in the regulation of immune and inflammatory responses, and the therapeutical modulation of this balance should represent part of advanced biological treatments for rheumatoid arthritis and other autoimmune rheumatic diseases.

Androgens↗

PubMed2002

Modulation of cell growth and apoptosis by sex hormones in cultured monocytic THP-1 cells.

Several authors have reported the regulation of apoptotic phenomena by sex hormones in different cell lines, including T lymphocytes and mononuclear cells. Since androgens can modulate the programmed cell death in responsive cell lines, we decided to investigate the induction of apoptosis in THP-1 cells following their differentiation into macrophage-like cells and exposure to sex hormones. In addition, we decided to evaluate the proto-oncogene Bax and Fas (CD 95) and cleaved PARP (poly-adp-ribose-polymerase) expression in the same cultured cells. The results showed for the first time the dose-/time-dependent regulation of the apoptotic event in human monocytic THP-1 cells treated with different concentrations of androgens. No significant changes were observed for estrogen-treated and unstimulated control cells. In particular, the cells, after stimulation with androgens but not with estrogens, were found to be positive for the proto-oncogene Bax, Fas, and for cleaved subunits of PARP expression as demonstrated with different assays including immunocytochemical assay and Western blot analysis. In conclusion, these results support the possibility of sex hormone modulation of apoptosis in macrophage-like cells, with interesting therapeutic perspectives in rheumatoid arthritis.

Apoptosis↗

PubMed2002

Antiproliferative-antiinflammatory effects of methotrexate and sex hormones on cultured differentiating myeloid monocytic cells (THP-1).

Methotrexate (MTX) is believed to exert both antiproliferative and antiinflammatory effects in a dose-related manner in a majority of rheumatoid arthritis (RA) patients along with an abrupt flare of the disease after drug discontinuation. To investigate the antiproliferative and antiinflammatory actions of MTX and the combined action of sex hormones, we evaluated these effects in differentiated monocytic myeloid cells (THP-1) prestimulated with testosterone (T) or 17-beta estradiol (E2). The effects of MTX and T combined treatment (T/MTX) on THP-1 cells showed a significant inhibition of cell proliferation when compared with E2/MTX- treated cells or controls: 53% at 72 h versus E2-treated cells; 58% at 96 h versus E2-treated cells; and 41% versus controls, respectively. Bax and Fas CD95 expression was found increased in T-treated cells: 14% T at 48 h vs. E(2)-treated cells and controls; 45% T at 72 h versus E2-treated cells and controls; 97% at 96 h versus E2-treated cells and 37% versus controls for Bax: 33%, 41%, and 42% T versus E2-treated cells for Fas. Moreover, a significant decrease of IL-12 levels in T/MTX treated cells was found at any time when compared to E2-treated cells. In summary, the association of testosterone and MTX compared to MTX alone suggests possible synergistic actions. Therefore, the enhancing antiinflammatory effects exerted by androgens might represent a further explanation for the reduced frequency of inflammatory diseases in male subjects.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2002

Serum prolactin concentrations in male patients with rheumatoid arthritis.

Altered serum prolactin (PRL) levels have been reported in autoimmune diseases; however, data of serum PRL concentrations in rheumatoid arthritis (RA) are contradictory. We evaluated the PRL status in men affected by RA and the possible relationships among serum PRL levels, bone mass, and disease activity. We investigated 29 men affected by RA and 30 age- and sex-matched controls. All patients were evaluated for serum PRL levels, parameters of disease activity, and bone mineral density (BMD) at L2-L4 and the femoral neck. Serum PRL levels were found significantly higher in men with RA than in controls (p = 0.001). High serum PRL levels were significantly correlated with duration of RA and some laboratory parameters of RA disease activity. A negative correlation between femoral BMD and serum PRL levels were found (r = -0.821, p = 0.001). Male patients affected by RA showed high serum PRL levels. The serum PRL concentration was found to be increased in relation to the duration and the activity of the disease. Serum PRL levels do not seem to have any relationship with the BMD, at least in RA.

Absorptiometry, Photon↗

PubMed2002

Melatonin in rheumatoid arthritis: synovial macrophages show melatonin receptors.

The pineal neurohormone melatonin is widely recognized as exerting important immunoenhancing effects that act on specific receptors in immunocompetent cells. This action results in stimulation of cytokine production in lymphocytes and macrophages. Here we report that the nocturnal plasma concentration of melatonin in rheumatoid arthritis (RA) patients is higher than in healthy controls. Furthermore, melatonin is present in the synovial fluid of RA patients and synovial macrophages express a specific binding site. We suggest that melatonin may exert a disease-promoting role in RA.

Adult↗

PubMed2002

Serum osteocalcin levels in premenopausal rheumatoid arthritis patients.

The objective of this study was to assess the occurrence of generalized bone loss in rheumatoid arthritis (RA) patients and to evaluate the factors influencing bone loss, in particular, the usefulness of bone turnover markers. Twenty-five premenopausal patients (mean age, 40 x 5 years) with active RA were compared with 27 age-matched premenopausal patients with RA but without active disease and 30 age-matched healthy premenopausal controls. Serum concentrations of osteocalcin, intact parathyroid hormone (PTH), spot urine concentrations of crosslinked N-telopeptidases of type 1 collagen (NTX), and deoxypyridinoline (DPD) were detected by ELISA and radioimmunoassay. Serum osteocalcin levels were found to be significantly lower (p < 0.001) in patients with active RA compared with patients without active RA and controls. Similarly, serum intact PTH was significantly lower (p < 0.01) in patients with active RA than in patients with RA without active disease and controls. Spot urine concentrations of NTX and DPD were significantly higher (p < 0.01) in active RA patients than in patients with nonactive RA and controls. Positive correlations between osteocalcin and marker of disease activity were found to be significant (p < 0.01). There were no significant correlations between serum intact PTH, urine concentrations of NTX and DPD, and markers of inflammation. This study suggests that generalized bone loss occurs in active RA and is characterized by an evident bone resorption correlated with the high levels of inflammation.

Adult↗

PubMed2002

Adrenal gland hypofunction in active polymyalgia rheumatica. effect of glucocorticoid treatment on adrenal hormones and interleukin 6.

OBJECTIVE: To evaluate hypothalamic-pituitary-adrenal (HPA) axis function in patients with recent onset polymyalgia rheumatica (PMR) not previously treated with glucocorticoids; and to detect possible correlations between adrenal hormone levels, interleukin 6 (IL-6), and other acute phase reactants at baseline and during 12 months of glucocorticoid treatment. METHODS: Forty-one PMR patients of both sexes with recent onset disease and healthy sex and age matched controls were enrolled into a longitudinal study. Patients were monitored for serum cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione (ASD), and clinical and laboratory measures of disease activity such as C-reactive protein and IL-6 concentrations at baseline and after 1, 3, 6, 9 and 12 months of glucocorticoid treatment. To assess dynamic HPA axis function, serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were evaluated in another 8 patients with recent onset PMR not treated with glucocorticoid in comparison to controls after challenge with ovine corticotropin releasing hormone (oCRH) test. In addition, serum cortisol and 17-hydroxyprogesterone (17-OHP) levels were evaluated after stimulation with low dose (1 microg) intravenous ACTH. RESULTS: Serum cortisol and ASD levels of all PMR patients at baseline did not differ from controls. During followup, cortisol levels dipped at one and 3 months. Serum DHEAS levels in all patients were significantly lower than in controls at baseline. In female PMR patients a significant correlation was found at baseline between cortisol levels and duration of disease. Serum concentrations of IL-6 at baseline were significantly higher in PMR patients than in controls. During 12 months of glucocorticoid treatment IL-6 levels dropped significantly at one month; thereafter they remained stable and did not increase again despite tapering of the glucocorticoid dose. After oCRH stimulation, a similar cortisol response was found in patients and controls. After ACTH administration, a significant cortisol peak was detected in patients and controls, whereas no significant difference in cortisol area-under-the-curve (AUC) was found between the groups. In contrast, ACTH induced a significantly higher (p < 0.05) peak of 17-OHP and AUC in PMR patients than in controls. CONCLUSION: This study found reduced production of adrenal hormones (cortisol, DHEAS) at baseline in patients with active and untreated PMR. The defect seems mainly related to altered adrenal responsiveness to the ACTH stimulation (i.e., increased 17-OHP), at least in untreated patients. The 12 month glucocorticoid treatment of patients reduced the production of inflammatory mediators (i.e., IL-6) in a stable manner that persisted after glucocorticoids were tapered.

17-alpha-Hydroxyprogesterone↗