Dysregulation of the kallikrein-kinin system in bronchoalveolar lavage fluid of patients with severe COVID-19.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the angiotensin-converting enzyme 2 (ACE2) receptor, a critical component of the kallikrein-kinin system. Its dysregulation may lead to increased vascular permeability and release of inflammatory chemokines. Interactions between the kallikrein-kinin and the coagulation system might further contribute to thromboembolic complications in COVID-19.

Cytokine signalling in the beta-cell: a dual role for IFNgamma.

IFNgamma (interferon gamma), a cytokine typically secreted by infiltrating immune cells in insulitis in Type 1 diabetes, is by itself not detrimental to beta-cells, but, together with other cytokines, such as IL-1beta (interleukin 1beta) and TNFalpha (tumour necrosis factor alpha), or dsRNA (double-stranded RNA), it induces beta-cell apoptosis. The complex gene and protein networks that are altered by the combination of cytokines clearly point towards synergisms between these agents. IFNgamma acts mostly via JAK (Janus kinase) activation, with the transcription factors STAT-1 (signal transducer and activator of transcription-1) and IRF-1 (IFNgamma regulatory factor-1) playing a central role in the downstream pathway.

Deletion of STAT-1 pancreatic islets protects against streptozotocin-induced diabetes and early graft failure but not against late rejection.

Objective: Exposure of beta-cells to inflammatory cytokines leads to apoptotic cell death through the activation of gene networks under the control of specific transcription factors, such as interferon-gamma-induced signal transducer and activator of transcription (STAT)-1. We previously demonstrated that beta-cells lacking STAT-1 are resistant to cytokine-induced cell death in vitro. The aim of this study was to investigate the effect of STAT-1 elimination on immune-mediated beta-cell destruction in vivo.

Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells.

beta-cells under immune attack are destroyed by the aberrant activation of key intracellular signaling cascades. The aim of the present study was to evaluate the contribution of the signal transducer and activator of transcription (STAT)-1 pathway for beta-cell apoptosis by studying the sensitivity of beta-cells from STAT-1 knockout (-/-) mice to immune-mediated cell death in vitro and in vivo. Whole islets from STAT-1-/- mice were completely resistant to interferon (IFN)-gamma (studied in combination with interleukin [IL]-1beta)-mediated cell death (92 +/- 4% viable cells in STAT-1-/- mice vs.

1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice.

1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)) is an immune modulator that prevents experimental autoimmune diseases. Receptors for 1,25-(OH)(2)D(3) are present in pancreatic beta-cells, the target of an autoimmune assault in nonobese diabetic (NOD) mice. The aim of this study was to investigate the in vivo and in vitro effects of 1,25-(OH)(2)D(3) on beta-cell gene expression and death and correlate these findings to in vivo diabetes development in NOD mice.