Fibroblasts are the effector cells of fibrosis characteristic systemic sclerosis (SSc, scleroderma) and other fibrosing conditions. The excess production extracellular matrix (ECM) proteins is hallmark in different organs, such as skin lung. Experiments designed to assess pro-fibrotic capacity factors, their signaling pathways, potential inhibitors effects that conducted fibroblasts have paved way for planning clinical trials SSc. As such, proven be valuable tools search effective...

Sphingosine kinase 1 (SphK1) is an enzyme that converts sphingosine to bioactive sphingosine-1-phosphate. Recent in vitro data suggest a potential role of SphK1 TNF-alpha-mediated inflammation. Our aims this study were determine the vivo significance chronic inflammation and define which pathogenic mechanisms induced by TNF-alpha are dependent. To pursue these aims, we studied effect deficiency model TNF-alpha-induced inflammatory arthritis. Transgenic hTNF-alpha mice, develop spontaneous...

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with many clinical manifestations that lead to significant morbidity and mortality.The textbook, Lupus Erythematosus -Basic, Applied, Clinical Aspects, was written as thorough examination of the historic, pathogenetic, clinical, treatment dimensions SLE.Each these topics divided into sections, detailed chapters within each section.Each chapter by an international panel experts in particular topic it relates SLE.The beginning...

Systemic sclerosis (SSc) is a complex multi-system autoimmune disease characterized by immune dysregulation, vasculopathy, and organ fibrosis. Skin fibrosis causes high morbidity impaired quality of life in affected individuals. Animal models do not fully recapitulate the human disease. Thus, there critical need to identify ex vivo for dermal characteristic SSc. We identified genes regulated pro-fibrotic factor TGFβ skin maintained culture. The molecular signature overlapped with that which...

Systemic sclerosis (SSc) is a female-predominant disease, characterized by excessive extracellular matrix deposition (ECM) with dermal and internal organ fibrosis. Considering the sex-based disparity in disease incidence, estradiol (E2), an estrogen form pro-fibrotic effects, may play role SSc. We reported that post-menopausal women diffuse cutaneous (dc)SSc have higher serum E2 levels compared to similar aged, healthy controls. Since males SSc tend more severe we examined dcSSc relation...

The etiology and reasons underlying the ethnic disparities in systemic sclerosis (SSc) remain unknown. African Americans are disproportionally affected by SSc yet underrepresented research. aim of this study was to comprehensively investigate association DNA methylation levels with dermal fibroblasts from patients ancestry. Reduced representation bisulfite sequencing (RRBS) performed on primary 15 controls ancestry, over 3.8 million CpG sites were tested for differential patterns between...

In the skin, estradiol (E2) promotes profibrotic and proinflammatory cytokines, contributing to extracellular matrix (ECM) deposition. However, magnitude of response differs. Using human skin organ culture model, we evaluated donor characteristics correlations that contribute E2-induced interleukin-6 (IL-6), transforming growth factor beta 1 2 (TGFB1 TGFB2), collagen IA2 (Col IA2), IIIA1 IIIA1), fibronectin (FN) expressions. vehicle- E2-treated dermal tissue transcripts, confirm differences...

Gelsolin, an actin capping protein of osteoclast podosomes, has a unique function in regulating assembly and disassembly the podosome filament. Previously, we have reported that osteopontin (OPN) binding to integrin αvβ3 increased levels gelsolin-associated polyphosphoinositides, assembly/disassembly, filament formation. The present study was undertaken identify possible role polyphosphoinositides phosphoinositides domains (PBDs) gelsolin cytoskeletal structural organization function....

Both TGFβ and estradiol (E2), a form of estrogen, are pro-fibrotic in the skin. In connective tissue disease, systemic sclerosis (SSc), both E2 likely pathogenic. Yet regulation E2-induced dermal fibrosis remains ill-defined. Elucidating those regulatory mechanisms will improve understanding fibrotic disease pathogenesis set stage for developing potential therapeutics. Using E2-stimulated primary human fibroblasts vitro skin ex vivo, we identified important proteins investigated...

Lupus disease measures such as the Systemic Erythematosus Disease Activity Index (SLEDAI) and British Isles Assessment Group (BILAG) index are challenging to interpret. The Foundation of America-Rapid Evaluation in (LFA-REAL) is intended provide an efficient application anchored visual analog scores, each representing individual severity active symptoms, with sum scores deriving overall activity assessment. Our objective was compare performance LFA-REAL systemic lupus erythematosus...

Abstract Background Systemic sclerosis (SSc) is a multisystem autoimmune disorder that has an unclear etiology and disproportionately affects women African Americans. Despite this, Americans are dramatically underrepresented in SSc research. Additionally, monocytes show heightened activation relative to European In this study, we sought investigate DNA methylation gene expression patterns classical health disparity population. Methods Classical (CD14+ + CD16−) were FACS-isolated from 34...

Systemic sclerosis (SSc) is characterized by dermal fibrosis with a female predominance, suggesting hormonal influence. Patients SSc have elevated interleukin (IL)-6 levels, and post-menopausal women older men also high estradiol (E2) levels. In the skin, IL-6 increases enzymatic activity of aromatase, thereby amplifying conversion testosterone to E2. Therefore, we hypothesized that an interplay between E2 contributes fibrosis. We used primary fibroblasts from healthy donors patients diffuse...

Sphingolipids are mediators of inflammation; changes in their cellular concentration modulate specific functions. Investigations sphingosine kinases (SphK) and 1 phosphate (S1P) TNFα driven murine models rheumatoid arthritis (RA), identified SphK/S1P as important intermediaries mediated synovial proinflammatory pathways. Fibroblast-like synoviocytes (FLS) key contributors to RA pathogenesis express both SphK 2. To pinpoint the mechanisms effects inflammatory response FLS vitro, we derived...

OBJECTIVES/SPECIFIC AIMS: Our objective was to examine serum E2 levels in dcSSc males relation disease characteristics (i.e autoanitbody profile and internal organ involvement) its impact on survival. METHODS/STUDY POPULATION: We measured 83 men >50 years old from the University of Pittsburgh Scleroderma Center healthy controls similar age. Using statistical modeling, we examined associations between circulating levels, involvement, autoantibody profiles, RESULTS/ANTICIPATED RESULTS: Male...

ABSTRACT Objective The etiology and reasons underlying the ethnic disparities in systemic sclerosis (SSc) remain unknown. African Americans are disproportionally affected by SSc, yet underrepresented research. aim of this study was to comprehensively investigate association DNA methylation levels with SSc dermal fibroblasts from patients ancestry. Methods Reduced representation bisulfite sequencing (RRBS) performed on primary cultured 15 controls ancestry, over 3.8 million CpG sites were...

Abstract We demonstrate an estrogen independent involvement of ERα in TLR2 mediated expression MCP1 mesangial cells. In vitro treatment with the ligands Pam3CysSK4, LTA and PGN-SA induced production cells isolated from kidneys female C57BL/6 mice a dose dependent manner. Treatment to was found activate NF kB its nuclear localization. Interestingly enough, we phosphorylation primary also SV40 virus transformed B6 cell line. Nuclear translocation pERα (Ser118) treated selective antagonist MPP...

Abstract Activation of B cells is hall mark protective immune responses against pathogens. A wide range antigen(s) and differences in mode recognition these antigens confer diversified adaptive infection, autoimmune disease like lupus or allergy. Our initial observations via flow cytometry indicated a shift CD19+ spleens female C57BL/6 mice injected TLR2 ligand LTA the intraperitoneal route as compared to control received sterile PBS. The spleen demonstrated population which also found...

Abstract Changes in sphingolipid levels can alter cellular functions. Sphingosine 1 phosphate (S1P) and hTNF stimulates COX-2 PGE2 fibroblast-like synoviocytes (FLS). In vitro, S1P both produce more than either separately. Blocking sphingosine kinase 1(SphK1) decreases after stimulation. Our hypothesis is mice overexpressing without functional SphK1 (hTNF/SphK1-/-) will have less synovial inflammation that overexpress with (hTNF/SphK1+/+). Transgenic were crossed SphK1-/- mice, genotyped...

Abstract Background: Both TGFb and estradiol (E2), a form of estrogen, are pro-fibrotic in the skin. In connective tissue disease, systemic sclerosis (SSc), both E2 likely pathogenic. Yet, regulation E2-induced dermal fibrosis remains ill-defined. Elucidating those regulatory mechanisms will improve understanding fibrotic disease pathogenesis set stage for developing potential therapeutics. Using E2-stimulated primary human fibroblasts vitro skin ex vivo , we identified important proteins...