It was recently demonstrated that interleukin (IL)-23–driven IL-17–producing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction of antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type I–deficient (IL-1RI−/−) mice. Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI−/− compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different. However, EAE was induced in IL-1RI−/− mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23 alone did not induce IL-17 production by T cells from IL-1RI−/− mice, and IL-23–induced IL-17 production was substantially enhanced by IL-1α or IL-1β, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor κB, and novel protein kinase C isoforms in IL-1– and IL-23–mediated IL-17 production. Tumor necrosis factor α also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE.
Background Qualitative descriptive designs are common in nursing and healthcare research due to their inherent simplicity, flexibility and utility in diverse healthcare contexts. However, the application of descriptive research is sometimes critiqued in terms of scientific rigor. Inconsistency in decision making within the research process coupled with a lack of transparency has created issues of credibility for this type of approach. It can be difficult to clearly differentiate what constitutes a descriptive research design from the range of other methodologies at the disposal of qualitative researchers. Aims This paper provides an overview of qualitative descriptive research, orientates to the underlying philosophical perspectives and key characteristics that define this approach and identifies the implications for healthcare practice and policy. Methods and results Using real-world examples from healthcare research, the paper provides insight to the practical application of descriptive research at all stages of the design process and identifies the critical elements that should be explicit when applying this approach. Conclusions By adding to the existing knowledge base, this paper enhances the information available to researchers who wish to use the qualitative descriptive approach, influencing the standard of how this approach is employed in healthcare research.
Background-Reperfusion therapy for myocardial infarction is hampered by detrimental inflammatory responses partlyvia Toll-like receptor (TLR) activation. Targeting TLR signaling may optimize reperfusion therapy and enhance cell survival and heart function after myocardial infarction. Here, we evaluated the role of TLR2 as a therapeutic target using a novel monoclonal anti-TLR2 antibody. Method and Results-Mice underwent 30 minutes of ischemia followed by reperfusion. Compounds were administered 5 minutes before reperfusion. Cardiac function and dimensions were assessed at baseline and 28 days after infarction with 9.4-T mouse magnetic resonance imaging. Saline and IgG isotype treatment resulted in 34.5Ϯ3.3% and 31.4Ϯ2.7% infarction, respectively. Bone marrow transplantation experiments between wild-type and TLR2-null mice revealed that final infarct size is determined by circulating TLR2 expression. A single intravenous bolus injection of anti-TLR2 antibody reduced infarct size to 18.9Ϯ2.2% (Pϭ0.001). Compared with saline-treated mice, anti-TLR2-treated mice exhibited less expansive remodeling (end-diastolic volume 68.2Ϯ2.5 versus 76.8Ϯ3.5 L; Pϭ0.046) and preserved systolic performance (ejection fraction 51.0Ϯ2.1% versus 39.9Ϯ2.2%, Pϭ0.009; systolic wall thickening 3.3Ϯ6.0% versus 22.0Ϯ4.4%, Pϭ0.038). Anti-TLR2 treatment significantly reduced neutrophil, macrophage, and T-lymphocyte infiltration. Furthermore, tumor necrosis factor-␣, interleukin-1␣, granulocyte macrophage colony-stimulating factor, and interleukin-10 were significantly reduced, as were phosphorylated c-jun N-terminal kinase, phosphorylated p38 mitogen-activated protein kinase, and caspase 3/7 activity levels. Conclusions-Circulating TLR2 expression mediates myocardial ischemia/reperfusion injury. Antagonizing TLR2 just 5 minutes before reperfusion reduces infarct size and preserves cardiac function and geometry. Anti-TLR2 therapy exerts its action by reducing leukocyte influx, cytokine production, and proapoptotic signaling. Hence, monoclonal anti-TLR2 antibody is a potential candidate as an adjunctive for reperfusion therapy in patients with myocardial infarction. (Circulation. 2010;121:80-90.)Key Words: immune system Ⅲ inflammation Ⅲ myocardial infarction Ⅲ reperfusion Ⅲ Toll-like receptors E arly restoration of blood flow through the occluded coronary artery is currently the most effective therapy to limit infarct size and to preserve cardiac function and geometry after acute myocardial infarction (MI). 1 Nevertheless, reperfusion alone is insufficient to save endangered myocardium because complications resulting from loss of viable myocardium are still common after MI even after restoration of blood flow. Furthermore, studies have clearly demonstrated that reperfusion after ischemia causes additional cell death and increases infarct size (IS), called myocardial ischemia/reperfusion (I/R) injury. Many interventions aiming at reducing myocardial I/R injury have been proven to be successful in experimental studies but have failed in clinical se...
Signaling through Toll-like receptors (TLR) activates dendritic cell (DC) maturation and IL-12 production, which directs the induction of Th1 cells. We found that the production of IL-10, in addition to inflammatory cytokines and chemokines, was significantly reduced in DCs from TLR4-defective C3H/HeJ mice in response to Bordetella pertussis. TLR4 was also required for B. pertussis LPS-induced maturation of DCs, but other B. pertussis components stimulated DC maturation independently of TLR4. The course of B. pertussis infection was more severe in C3H/HeJ than in C3H/HeN mice. Surprisingly, Ab- and Ag-specific IFN-γ responses were enhanced at the peak of infection, whereas Ag-specific IL-10-producing T cells were significantly reduced in C3H/HeJ mice. This was associated with enhanced inflammatory cytokine production, cellular infiltration, and severe pathological changes in the lungs of TLR4-defective mice. Our findings suggest that TLR-4 signaling activates innate IL-10 production in response to B. pertussis, which both directly, and by promoting the induction of IL-10-secreting type 1 regulatory T cells, may inhibit Th1 responses and limit inflammatory pathology in the lungs during infection with B. pertussis.
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