Increased sensitivity to interferon-alpha in psoriatic T cells

Psoriasis is a chronic inflammatory skin disease characterized by abnormal epidermal proliferation. Several studies have shown that skin-infiltrating activated T cells and cytokines play a pivotal role during the initiation and maintenance of the disease. Interferon (IFN)-α plays an important role in host defense against infections, but recent data have also implicated IFN-α in psoriasis. Thus, IFN-α induces or aggravates psoriasis in some patients, and mice lacking a transcriptional attenuator of IFN-α/β signaling spontaneously develop a psoriasis-like inflammatory skin disease characterized by CD8+-infiltrating T cells. In this study, we therefore investigate IFN-α signaling in T cells isolated from involved skin of psoriatic patients. We show that psoriatic T cells have increased and prolonged responses to IFN-α, on the level of signal transducers and activators of transcription (STAT) activation, compared with infiltrating T cells from skin of non-psoriatic donors. Functionally, the increased IFN-α signaling leads to an increased binding of STAT4 to the IFN-γ promotor, IFN-γ production, and inhibition of T cell growth. In contrast, to STAT responses to other cytokines were not changed in psoriasis. In conclusion, we provide evidence that psoriatic T cells have an increased sensitivity to IFN-α. Thus, our data suggest that increased IFN-α signaling is involved in the pathogenesis of psoriasis

Malignant cutaneous T-cell lymphoma cells express IL-17 utilizing the Jak3/Stat3 signaling pathway

IL-17 is a proinflammatory cytokine that is crucial for the host's protection against a range of extracellular pathogens. However, inappropriately regulated expression of IL-17 is associated with the development of inflammatory diseases and cancer. In cutaneous T-cell lymphoma (CTCL), malignant T cells gradually accumulate in skin lesions characterized by massive chronic inflammation, suggesting that IL-17 could be involved in the pathogenesis. In this study we show that IL-17 protein is present in 10 of 13 examined skin lesions but not in sera from 28 CTCL patients. Importantly, IL-17 expression is primarily observed in atypical lymphocytes with characteristic neoplastic cell morphology. In accordance, malignant T-cell lines from CTCL patients produce IL-17 and the synthesis is selectively increased by IL-2 receptor β chain cytokines. Small-molecule inhibitors or small interfering RNA against Jak3 and signal transducer and activator of transcription 3 (Stat3) reduce the production of IL-17, showing that the Jak3/Stat3 pathway promotes the expression of the cytokine. In summary, our findings indicate that the malignant T cells in CTCL lesions express IL-17 and that this expression is promoted by the Jak3/Stat3 pathway

Outcomes in Newly Diagnosed Atrial Fibrillation and History of Acute Coronary Syndromes: Insights from GARFIELD-AF

BACKGROUND: Many patients with atrial fibrillation have concomitant coronary artery disease with or without acute coronary syndromes and are in need of additional antithrombotic therapy. There are few data on the long-term clinical outcome of atrial fibrillation patients with a history of acute coronary syndrome. This is a 2-year study of atrial fibrillation patients with or without a history of acute coronary syndromes