ABSTRACT
Pathogenesis of primary Sjögren's syndrome (SjS) remains obscure. However, recent data demonstrate the implication of epigenetic alterations in the DNA methylation/hydroxymethylation process in SjS mostly affecting genes regulated by two innate cytokines, interferon α (IFNα) and IFNγ as well as the oxidative stress pathways. The Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway is known to be activated by IFN and reactive oxygen species (ROS). This prompts us to test the potential implication of JAK/STAT signaling on DNA methylation/hydroxymethylation alterations in SjS. For this purpose, the human salivary gland (HSG) cell line was used and cells were treated with both types of IFNs and H2O2 to mimic activated salivary gland epithelial cells (SGEC) as observed in SjS patients. Afterwards, the global DNA level of methylcytosine and hydroxymethylcytosine, the expression of the DNA methylating enzymes (DNMTs) and ten-eleven translocation (TETs) methyl cytosine dioxygenase that controls DNA hydroxymethylation, both at transcriptional and at protein level, as well as STAT phosphorylation and ROS status were determined. Our results showed that expression of TET3 and in turn global DNA hydroxymethylation is controlled through the induction of STAT3 mediated by IFNα, IFNγ, and H2O2. On the other hand, treatment with JAK inhibitors (AG490 and ruxolitinib) reverses this process, suggesting a novel treatment pathway for patients with autoimmune diseases and Sjögren's syndrome.
Subject(s)
Cellular Reprogramming/drug effects , Cellular Reprogramming/genetics , Epigenesis, Genetic/drug effects , Immunity, Innate/drug effects , Janus Kinase Inhibitors/therapeutic use , Sjogren's Syndrome/drug therapy , Sjogren's Syndrome/etiology , DNA Methylation/drug effects , Gene Expression Profiling , Gene Expression Regulation, Enzymologic , Humans , Hydrogen Peroxide/metabolism , Janus Kinase Inhibitors/pharmacology , Janus Kinases/metabolism , Models, Biological , Phosphorylation , Reactive Oxygen Species/metabolism , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Sjogren's Syndrome/metabolismABSTRACT
Primary Sjögren's syndrome (SjS) is a complex autoimmune epithelitis, with few treatment options, but the use of Janus kinase (JAK) inhibitors is promising because suppression of the JAK/signal transducer and activator of transcription (STAT) pathway improves sicca manifestations. Playing a primary and pathogenic role in disease development, the oxidative stress response is upregulated in activated salivary gland epithelial cells (SGECs) from patients with SjS. Therefore, the aim of this study was to investigate whether JAK inhibitors would suppress SGEC activation in response to an oxidative stress. For this purpose, the human salivary gland (HSG) cell line was used, and cells were treated with the reactive oxygen species (ROS) inducer hydrogen peroxide (H2O2) or with interferons (IFN Type I and Type II), used as positive controls, to mimic activated SGECs as observed in SjS patients. Afterward, the levels of the intracellular adhesion molecule-1 (ICAM-1) and the regulatory programmed-death ligand-1 (PD-L1) were measured by real-time PCR and flow cytometry, and the STAT1/3 phosphorylation status was assessed by Western blotting. Using the HSG cell line, our results showed that both ICAM-1 and PD-L1 are induced by ROS through pSTAT3, and that this activation pathway is reversed by the use of JAK inhibitors, AG490 and ruxolitinib, as well as by N-acetylcysteine, which is a direct inhibitor of ROS. These findings open new perspectives regarding the pathogenesis and therapeutic possibilities for SjS.
Subject(s)
Janus Kinase Inhibitors/pharmacology , Oxidative Stress/drug effects , B7-H1 Antigen/metabolism , Biomarkers , Cell Line , Gene Expression Regulation , Humans , Intercellular Adhesion Molecule-1/metabolism , Models, Biological , Oxidative Stress/genetics , Phosphorylation , Reactive Oxygen Species/metabolism , STAT1 Transcription Factor/metabolism , STAT3 Transcription Factor/metabolismABSTRACT
Autoimmune hepatitis (AIH) is a progressive, chronic liver disease characterized by unresolving hepatocellular inflammation of autoimmune origin. The clinical spectrum may vary from asymptomatic presentation, to non-specific symptoms such as fatigue, arthralgias, nausea and abdominal pain, to acute severe liver disease. AIH is characterized by the presence of interface hepatitis and portal plasma cell infiltration on histological examination, hypergammaglobulinemia, and positive autoantibodies. AIH is associated with other autoimmune diseases and its course is often accompanied by various non-specific hematological disorders. However, the coexistence of autoimmune neutropenia (AIN) is infrequent. We present a case of a female patient diagnosed with type 1 AIH and agranulocytosis on presentation. A diagnosis of AIN was established, based on the patient's sex, the underlying liver disease, the absence of alternative causes, the presence of atypical anti-neutrophil cytoplasmic antibodies in patient's serum and the favorable and dose-dependent treatment of both pathologic entities with corticosteroids and mycophenolate mofetil.