Co-culture system of human salivary gland epithelial cells and immune cells from primary Sjögren's syndrome patients: an in vitro approach to study the effects of Rituximab on the activation of the Raf-1/ERK1/2 pathway.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates in the affected glands. Dryness of the mouth and eyes results from involvement of the salivary and lacrimal glands. The efficacy of Rituximab (RTX) in pSS is still open to debate.

ADAM17 at the interface between inflammation and autoimmunity.

The discovery of the disintegrin and metalloproteinase 17 (ADAM17), originally identified as tumor necrosis factor-a converting enzyme (TACE) for its ability as sheddase of TNF-α inspired scientists to attempt to elucidate the molecular mechanisms underlying ADAM17 implication in diseased conditions. In recent years, it has become evident that this protease can modify many non matrix substrates, such as cytokines (e.g.

Neovascularization is prominent in the chronic inflammatory lesions of Sjögren's syndrome.

Angiogenesis is a common finding in chronic inflammatory diseases; however, its role in Sjögren's syndrome (SS) remains to be elucidated. Previous SS studies have demonstrated an increase in VEGF-A/VEGFR-2 system expression in minor salivary gland (MSG) biopsies from patients with SS, but differences in the new blood vessel formation between the different grades of disease severity have not been reported. Therefore, experiments were performed to demonstrate angiogenesis during different phases of primary SS (pSS) and to define the relationship between the microvessel density (MVD), macrophage infiltration and histiocyte distribution in SS MSG inflammatory lesions.

The metalloproteinase ADAM17 and the epidermal growth factor receptor (EGFR) signaling drive the inflammatory epithelial response in Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder that particularly compromises the function of exocrine glands. The pathogenetic mechanisms of this autoimmune exocrinopathy have not been fully elucidated. Since increasing evidence actually suggests that the epidermal growth factor receptor (EGFR) pathway has a major impact on the inflammatory/immune reactions of the epithelial cells, in the apparent effort of enhancing innate immune defense while opposing overactivation of pro-inflammatory functions, the focus of the work presented here is clarify whether the EGFR-extracellular-signal-regulated kinase (ERK) pathway plays a role in the pro-inflammatory responses mounted by pSS salivary gland epithelial cells (SGEC).

Rituximab-mediated Raf kinase inhibitor protein induction modulates NF-κB in Sjögren syndrome.

Primary Sjögren syndrome (pSS) is an autoimmune disorder characterized by an epithelial injury surrounded by dense lymphocytic infiltrates. The conditions for the long-term maintenance of human salivary gland epithelial cells from pSS patients and a co-culture system with pSS lymphocytes were used to assess the effect of Rituximab (RTX) on the inflammatory condition and progression in pSS. Quantitative real-time PCR, genes and protein array analysis, Western blot, flow cytometry, small interfering RNA transfection and nuclear factor-κB (NF-κB) DNA binding assays were used as methods.

Chronic inflammation enhances NGF-β/TrkA system expression via EGFR/MEK/ERK pathway activation in Sjögren's syndrome.

Unlabelled: Primary Sjögren's syndrome (pSS) is a chronic autoimmune exocrine disease associated with variable lymphocytic infiltration of the affected organs (primarily salivary and lachrymal glands). To investigate the potential implication of nerve growth factor-β (NGF-β) and its high affinity receptor tyrosine kinase receptor A (TrkA) in the regulation of pSS inflammatory responses, we studied their expression in the human salivary gland epithelial cells (SGEC) cultures from pSS minor salivary glands (MSG) biopsies and their relationship with histopathological disease parameters. Here, we demonstrated an increased expression of the NGF-β/TrkA system in pSS SGEC, correlated with the MSG inflammation grade.

[Paget's disease of bone: new therapeutic strategies].

Paget's disease of bone is a chronic disorder of unknown etiology that can result in enlarged and misshapen bones. The excessive breakdown and formation of bone tissue cause affected bones to weaken, resulting in pain, misshapen bones, fractures, and arthritis in the joints. In most cases the diagnosis is achieved casually, as only 5% of patients develop burning pain at the level of affected bones.

GRO-α/CXCR2 system and ADAM17 correlated expression in Sjögren's syndrome.

The chemokine GRO-α and its receptor CXCR2 are associated with the chronic inflammation in Sjögren's syndrome (SS). To better understand the molecular mechanisms by which the GRO-α/CXCR2 system is involved in the SS inflammatory condition, our studies were designed to clarify the role of ADAM17 activation in the modulation of the GRO-α/CXCR2 chemokine system in epithelial cells (SGEC) from SS salivary glands. The CXCR2 overexpression observed in SS SGEC was dramatically decreased by ADAM17 inhibitor TAPI-1.

Salivary gland expression level of IκBα regulatory protein in Sjögren's syndrome.

Diagnosis and therapeutic strategies in Sjögren's syndrome (SS) might greatly benefit of the present multidisciplinary approach to studying the molecular pathogenesis of the disease. A deregulated inflammatory response has been described in the SS. The research in the last years sheds light on the importance of the NF-κB pathway regulating the pro-inflammatory cytokine production and leukocyte recruitment.

Emerging avenues linking inflammation, angiogenesis and Sjögren's syndrome.

Sjögren's syndrome (SS) is an autoimmune disease characterized by an inflammatory mononuclear infiltration and the destruction of epithelial cells of the lachrymal and salivary glands. The aetiology is unknown. The expression "autoimmune epithelitis" has been proposed as an alternative to SS, in view of the emerging central role of the epithelial cells in the disease pathogenesis.

Saponins from Tribulus terrestris L. protect human keratinocytes from UVB-induced damage.

Chronic exposure to solar UVB radiation damages skin, increasing the risk to develop cancer. Hence the identification of compounds with a photoprotective efficacy is essential. This study examined the role of saponins derived from Tribulus terrestris L.

A potential role of the GRO-α/CXCR2 system in Sjögren's syndrome: regulatory effects of pro-inflammatory cytokines.

Chemokines, small pro-inflammatory cytokines, are involved in migration of inflammatory cells in inflamed tissues and recent studies established their role in angiogenesis, hematopoiesis, cancer and autoimmune conditions. Growth related oncogene-alpha (GRO-α), a member of the CXC chemokine family, and its receptor CXCR2 are involved in the inflammatory processes. Since there is no previous report that supports a possible role of GRO-α/CXCR2 receptor complex during inflammation and neovascularization existing in the autoimmune disease Sjögren's syndrome (SS), in this study, we examined CXCR2 and its ligand GRO-α expression in SS tissues.

Altered IκBα expression promotes NF-κB activation in monocytes from primary Sjögren's syndrome patients.

Aims: To study the importance of IκBα in NF-κB signal transduction, we analysed the IκBα expression in monocytes from Sjögren's syndrome (SS) patients versus healthy controls.

Methods: Monocytes were obtained from the peripheral blood of 30 SS patients and 23 healthy subjects. IκBα expression was studied by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), real-time PCR, immunoblotting, flow cytometry and enzyme linked immunosorbent assay (ELISA).

Neuropilin-1 is upregulated in Sjögren's syndrome and contributes to pathological neovascularization.

Neuropilin-1 (NRP1) is a transmembrane co-receptor for members of the vascular endothelial growth factor family. Recent studies revealed an important role of NRP1 in angiogenesis and progression of many diseases. The role of NRP1 in the development of Sjögren's syndrome (SS), one of the most common rheumatic diseases, has not yet been investigated.

Sjögren's syndrome autoantibodies provoke changes in gene expression profiles of inflammatory cytokines triggering a pathway involving TACE/NF-κB.

We explore the association of the inflammatory gene expression profile observed in the chronic inflammatory autoimmune disorder Sjögren's syndrome (SS) with changes in TNF-α converting enzyme (TACE), tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB levels showing that pathways that include TNF-α signaling converge on NF-κB contributing to exacerbate the diseases. The treatment of human salivary gland epithelial cells (SGECs) with SS anti-Ro/SSA autoantibodies (Abs) result in a progressive increase in NF-κB-DNA binding, that includes a marked enhancement in NF-κB subunit p65 protein-DNA binding. A human cytokine multi-analyte array demonstrated that the NF-κB proinflammatory target genes, increased by anti-Ro/SSA Abs treatment, includes CXC chemokines (CXCL1, CXCL6 and CXCL9), CC chemokines (CCL2, CCL13 and CCL20), interleukins (IL-1α, IL-1β, IL-1F8, IL-6, IL-8, IL-9, IL-13, IL-17 and IL-22) and their receptors (IL-1RN, IL-10Rα, IL-13Rα, CCR1, CCR2, CCR3, CCR4 and CXCR1).

A failure of TNFAIP3 negative regulation maintains sustained NF-κB activation in Sjögren's syndrome.

Sjögren's syndrome (SS) is characterized by the features of systemic autoimmunity and exocrine gland dysfunction and inflammation. Deregulated cytokine production is known to contribute to the etiology of SS but the underlying molecular mechanism is still remains to be unclear. TNF-α-induced protein 3 or TNFAIP3 is involved in the negative feedback regulation of nuclear factor-κB (NF-κB) signaling in response to specific pro-inflammatory stimuli in different cell types.

[The treatment of the glucocorticoids-induced osteoporosis: recent knowledge].

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fractures that affects both cortical bone and trabecular bone. Osteoporosis may be either primary or secondary. Among the secondary forms, the glucocorticoid-induced osteoporosis is most common form that occurs, regardless of age, sex, and even with low doses of glucocorticoid.

RETRACTED: Blockade of TNF-α signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies.

The aim of this study was to analyze the Furin-TNF-α-converting enzyme (TACE)-amphiregulin (AREG)-IL-6/IL-8 secretion pathway in non-neoplastic human salivary gland epithelial cells (SGECs) stimulated with anti-Ro/SSA autoantibodies (Abs). We examined whether anti-Ro/SSA Abs-mediated TACE activation is responsible for AREG activation. As recent studies have demonstrated that AREG could induce proinflammatory cytokines secretion in epithelial cells, we discuss how TACE-mediated AREG shedding, caused by anti-Ro/SSA Abs treatment, could have a critical role in TNF-α-induced IL-6 and IL-8 secretion by SGEC.

Expression of pro-inflammatory TACE-TNF-α-amphiregulin axis in Sjögren's syndrome salivary glands.

The tumor-necrosis-factor-converting-enzyme (TACE)-TNF-α-Amphiregulin (AREG) axis plays an important pathogenic role in inflammatory and autoimmune disorders. However, the pathological roles of these proteins in the chronic autoimmune disease Sjögren's syndrome (SS) remain to be elucidated. It is known that the TACE-AREG axis is clearly part of a larger cascade of signals that starts with the activation of Furin, responsible for maturation of TACE that, in turn, determines the production of active TNF-α, directly involved in the up-regulation of AREG expression.

Pro-inflammatory role of Anti-Ro/SSA autoantibodies through the activation of Furin-TACE-amphiregulin axis.

Prolonged inflammation can be detrimental because it may cause host toxicity and tissue damage. Indeed, excessive production of inflammatory cytokines is often associated with many autoimmune diseases. In this study we demonstrate that the anti-Ro/SSA autoantibodies (Abs) stimulate the production of pro-inflammatory cytokines IL-6 and IL-8 by human healthy salivary gland epithelial cells (healthy SGEC).

Proposing a relationship between Mycobacterium avium subspecies paratuberculosis infection and Hashimoto's thyroiditis.

Humans are widely exposed to Mycobacterium avium subspecies paratuberculosis (MAP), a proven multi-host chronic enteric pathogen that has recently been linked to autoimmune diabetes. In the present study we used a MAP species-specific polymerase chain reaction with the insertion element IS900-specific probe to detect MAP infection in members of the same family suffering from Hashimoto's thyroiditis.

TNF blocker drugs modulate human TNF-α-converting enzyme pro-domain shedding induced by autoantibodies.

Novel biologic therapies targeted against specific components of the immune system, including blockade of TNF-α have revolutionized therapeutic approaches to inflammatory conditions and systemic inhibitors of TNF-α have been approved for the treatment of a wide variety of autoimmune diseases. No studies aimed to elucidate the effects of anti-TNF-α blockers on tumour necrosis factor-α convertase (TACE) expression and activation have yet been published. TACE is the principal protease involved in the activation of pro-TNF-α and is a target for anti-TNF-α therapy.

Regulation of mRNA caspase-8 levels by anti-nuclear autoantibodies.

Apoptosis of the acinar and ductal epithelial cells of the salivary glands has been proposed as a mechanism possibly responsible for the impairment of the secretory function in Sjögren's syndrome, an organ-specific autoimmune disorder characterized by destruction of these glandular structures. The presence of serum autoantibodies (Abs) directed against the ribonucleoproteic antigens Ro and La is one of the classification criteria used to identify Sjögren patients, and there is increasing evidence of the direct involvement of Abs in tissue pathogenesis. Our recent report demonstrated that anti-Ro and anti-La Abs are able to trigger the extrinsic pathway of apoptosis in the human salivary gland cells.

[New and old strategies against osteoporosis].

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture that affects both cortical bone and trabecular bone. Osteoporosis may be either primary or secondary. Primary osteoporosis can be distinguished into two types: diffuse or local.