digoxin and Autoimmune-Diseases

Myocarditis is a poorly understood condition and its prevalence is largely underestimated. A significant proportion of cases may be subclinical and chronic, leading to dilated cardiomyopathy, which represents the first cause of heart transplantation worldwide. Although inflammation of the myocardium can be associated with various causes, particularly viruses, myocarditis is usually idiopathic. Present evidence suggests that some 'idiopathic' and chronic 'postviral' myocarditis cases may be autoimmune, whereas others with acute self-limited disease or with persisting pathogenic virus by molecular methods may represent viral myocarditis. The major obstacle in identifying a specific therapy in myocarditis lies in the difficulty of a thorough clinical characterisation of individual patients in relation to viral and autoimmune involvement. This also explains the inconclusive results of trials of immunosuppressive drugs in myocarditis/dilated cardiomyopathy. Diagnosis is based upon endomyocardial biopsy. Management of myocarditis requires avoidance of agents that exacerbate myocarditis or depress myocardial function, and conventional therapy for heart failure (diuretics, ACE inhibitors and, if indicated, digoxin) and arrhythmias. Although at present the use of immunosuppressive therapy cannot be recommended on a routine basis, the recent Myocarditis Treatment Trial, where an aetiologically heterogeneous patient population was treated without significant adverse effects, provides some rationale for applying the same immunosuppression protocol to selected patients, e.g. those with active biopsy-proven myocarditis, unresponsive to conventional therapy, prior to transplantation, and those with idiopathic giant cell myocarditis.

Topics: Aging; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Autoimmune Diseases; Biopsy; Digoxin; Diuretics; Humans; Immunosuppressive Agents; Myocarditis; Virus Diseases

Digoxin is a cardiac glycoside that is commonly used to treat heart failure. Based on its known anti-inflammatory effect, this study was undertaken to investigate the effect of digoxin on collagen-induced arthritis (CIA) and to delineate the underlying mechanism. Digoxin or vehicle was injected intraperitoneally thrice weekly in mice with CIA, from day 7 or day 35 after immunization to investigate preventive or therapeutic effect, respectively. The incidence and severity of arthritis was evaluated. Digoxin treatment suppressed the incidence of arthritis and joint inflammation in mice with CIA. The expression of IL-17 and other proinflammatory cytokines, including IL-1β, IL-6, TNF-α and IL-21, were markedly reduced in the arthritic joints of digoxin-treated CIA mice. Th17 cells and CD4(+) pSTAT3(+) cells were less frequently observed in the spleen of digoxin-treated CIA mice than controls. The mRNA expression of IL-17 and ROR γt was consistently lower in total splenocytes or draining lymph node cells obtained from digoxin-treated CIA mice. Digoxin also reduced in vitro Th17 differentiation and LPS-stimulated IgG production. The number of osteoclasts in the arthritic joint was lower in digoxin-treated mice, whereas digoxin treatment did not directly suppress in vitro osteoclastogenesis. Our findings suggest that digoxin can regulate Th17 and reciprocally promote Treg cells and suppress joint inflammation and bone erosion in CIA. Digoxin may be a therapeutic option by targeting pathogenic Th17 and immunoglobulin production, for treatment of autoimmune arthritis and other Th17-related diseases.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Autoimmune Diseases; Cell Differentiation; Digoxin; Disease Models, Animal; Joints; Male; Mice, Inbred DBA; Th17 Cells

CD4(+) T helper lymphocytes that express interleukin-17 (T(H)17 cells) have critical roles in mouse models of autoimmunity, and there is mounting evidence that they also influence inflammatory processes in humans. Genome-wide association studies in humans have linked genes involved in T(H)17 cell differentiation and function with susceptibility to Crohn's disease, rheumatoid arthritis and psoriasis. Thus, the pathway towards differentiation of T(H)17 cells and, perhaps, of related innate lymphoid cells with similar effector functions, is an attractive target for therapeutic applications. Mouse and human T(H)17 cells are distinguished by expression of the retinoic acid receptor-related orphan nuclear receptor RORγt, which is required for induction of IL-17 transcription and for the manifestation of T(H)17-dependent autoimmune disease in mice. By performing a chemical screen with an insect cell-based reporter system, we identified the cardiac glycoside digoxin as a specific inhibitor of RORγt transcriptional activity. Digoxin inhibited murine T(H)17 cell differentiation without affecting differentiation of other T cell lineages and was effective in delaying the onset and reducing the severity of autoimmune disease in mice. At high concentrations, digoxin is toxic for human cells, but non-toxic synthetic derivatives 20,22-dihydrodigoxin-21,23-diol and digoxin-21-salicylidene specifically inhibited induction of IL-17 in human CD4(+) T cells. Using these small-molecule compounds, we demonstrate that RORγt is important for the maintenance of IL-17 expression in mouse and human effector T cells. These data indicate that derivatives of digoxin can be used as chemical templates for the development of RORγt-targeted therapeutic agents that attenuate inflammatory lymphocyte function and autoimmune disease.

Topics: Animals; Autoimmune Diseases; Autoimmunity; Cell Differentiation; Cell Line; Digoxin; Drosophila; Humans; Interleukin-17; Mice; Nuclear Receptor Subfamily 1, Group F, Member 3; Th17 Cells; Transcription, Genetic

Topics: Animals; Autoimmune Diseases; Autoimmunity; Cell Differentiation; Digoxin; Interleukin-17; Mice; Nuclear Receptor Subfamily 1, Group F, Member 1; Nuclear Receptor Subfamily 1, Group F, Member 3; Sulfonamides; Th17 Cells; Thiazoles

The retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORγt and suppressed Th17 differentiation without affecting Th1 differentiation. To better understand the structural basis for the inhibitory activity of digoxin, we determined the crystal structure of the RORγt ligand-binding domain in complex with digoxin at 2.2 Å resolution. The structure reveals that digoxin binds to the ligand-binding pocket protruding between helices H3 and H11 from the pocket. In addition, digoxin disrupts the key interaction important for the agonistic activity, resulting in preventing the positioning of helix H12 in the active conformation, thus antagonizing coactivator interaction. Functional studies demonstrated that digoxin inhibited RORγt activity and decreased IL-17 production but not RORα activity. Digoxin inhibited IL-17 production in CD4(+) T cells from experimental autoimmune encephalomyelitis mice. Our data indicates that RORγt is a promising therapeutic target for Th17-derived autoimmune diseases and our structural data will help to design novel RORγt antagonists.

Topics: Animals; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Cell Differentiation; Crystallography, X-Ray; Digoxin; Encephalomyelitis, Autoimmune, Experimental; Interleukin-17; Mice; Molecular Structure; Nuclear Receptor Subfamily 1, Group F, Member 3; Th17 Cells

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Autoimmune Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Ketoacidosis; Diagnosis, Differential; Digoxin; Female; Humans; Nausea; Weight Loss

Topics: Arrhythmias, Cardiac; Autoimmune Diseases; Coombs Test; Diagnosis; Digoxin; Drug Therapy; Geriatrics; Humans; Joint Diseases; Lupus Erythematosus, Systemic; Prednisone; Procainamide; Splenomegaly; Toxicology

Topics: Autoimmune Diseases; Betamethasone; Dexamethasone; Digoxin; Humans; Myocardial Infarction; Radiography, Thoracic; Syndrome; Warfarin