ABSTRACT
IL-32 expression is important for pathogen clearance but detrimental in chronic inflammation, autoimmunity, and cancer. T cells are major IL-32 producers in these diseases and key mediators of pathogen and tumor elimination but also autoimmune destruction. However, their contribution to IL-32 biology during immune responses is hardly understood due to several isoforms with divergent inflammatory properties. Here, we identified IL-32ß as the predominant isoform in various T cell subsets of healthy individuals and breast cancer patients with the highest levels detected in intratumoral regulatory T cells. We show that IL-32ß is induced by IL-2 but IL-32ß release requires T Cell Receptor rather than IL2R stimulation. Using inhibitors of protein secretion pathways and serial (ultra)centrifugation of T cell supernatants, we demonstrate that T cells actively secrete IL-32ß unconventionally, as a free protein and, to a minor degree, through exosomes. Thus, our data identify activated T cells as major IL-32ß secretors in health and cancer.
Subject(s)
Breast Neoplasms , Interleukin-2 , Interleukins , Lymphocyte Activation , Receptors, Antigen, T-Cell , Humans , Interleukins/metabolism , Interleukin-2/metabolism , Breast Neoplasms/immunology , Breast Neoplasms/metabolism , Female , Receptors, Antigen, T-Cell/metabolism , Receptors, Antigen, T-Cell/immunology , Lymphocyte Activation/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
INTRODUCTION AND OBJECTIVES: The effect of a centrifugal continuous-flow left ventricular assist device (cfLVAD) on hemodynamic left ventricular unloading (HLVU) and the clinical conditions that interfere with hemodynamic optimization are not well defined. METHODS: We retrospectively evaluated the likelihood of incomplete HLVU, defined as high pulmonary capillary wedge pressure (hPCWP)> 15mmHg in 104 ambulatory cfLVAD patients when the current standard recommendations for cfLVAD rotor speed setting were applied. We also evaluated the ability of clinical, hemodynamic and echocardiographic variables to predict hPCWP in ambulatory cfLVAD patients. RESULTS: Twenty-eight percent of the patients showed hPCWP. The variables associated with a higher risk of hPCWP were age, central venous pressure, absence of treatment with renin-angiotensin-aldosterone system inhibitors, and brain natriuretic peptide levels. Patients with optimal HLVU had a 15.2±14.7% decrease in postoperative indexed left ventricular end-diastolic diameter compared with 8.9±11.8% in the group with hPCWP (P=.041). Independent predictors of hPCWP included brain natriuretic peptide and age. Brain natriuretic peptide <300 pg/mL predicted freedom from hPCWP with a negative predictive value of 86% (P <.0001). CONCLUSIONS: An optimal HLVU can be achieved in up to 72% of the ambulatory cfLVAD patients when the current standard recommendations for rotor speed setting are applied. Age, central venous pressure and therapy with renin-angiotensin-aldosteron system inhibitors had a substantial effect on achieving this goal. Brain natriuretic peptide levels and the magnitude of reverse left ventricular remodeling seem to be useful noninvasive tools to evaluate HLVU in patients with functioning cfLVAD.