cyclic-gmp and Autoimmune-Diseases

Among the numerous genes controlled by cyclic adenosine monophosphate (cAMP)/protein kinase A signalling machinery is the gene encoding the inducible nitric oxide synthase (iNOS), an enzyme catalyzing the synthesis of a highly reactive free radical nitric oxide (NO). While being a major microbicidal and tumoricidal molecule, iNOS-derived NO has also been implicated in tissue destruction, as well as in regulation of inflammatory/immune cell function in various disorders associated with excessive inflammation. A feasible way for cAMP-dependent therapeutic control of inflammation, including iNOS-mediated NO synthesis, could involve the administration of drugs that block the enzymatic activity of cAMP-degrading phosphodiesterases (PDE). Indeed, cAMP-elevating PDE inhibitors can influence iNOS activation in different cell types in vitro, and their potent anti-inflammatory effects in experimental disease models and clinical studies were frequently accompanied with profound modulation of NO production. A set of conflicting data has been generated over the years, ranging from strong suppression to marked enhancement of NO release by cAMP-increasing PDE inhibitors, depending on cell-type, iNOS stimuli, and/or the agents used. The present review summarizes the data on iNOS modulation by cAMP-elevating PDE inhibitors and possible mechanisms behind it, speculating on its contribution to the therapeutic effects of these drugs.

Topics: Animals; Autoimmune Diseases; Clinical Trials as Topic; Cyclic AMP; Cyclic GMP; Enzyme Activation; Humans; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Phosphodiesterase Inhibitors; Shock, Septic

Topics: Antibody Formation; Autoimmune Diseases; Bacterial Infections; Carrier State; Communicable Diseases; Cyclic AMP; Cyclic GMP; Enzymes; Haptens; Humans; Immune Tolerance; Immunity, Cellular; Immunoglobulin A, Secretory

Type 17 helper T (Th17) cells are implicated in the pathogenesis many of human autoimmune diseases. Development of Th17 can be enhanced by the activation of aryl hydrocarbon receptor (AHR) whose ligands include the environmental pollutant dioxin, potentially linking environmental factors to the increased prevalence of autoimmune disease. We report here that nitric oxide (NO) can suppress the proliferation and function of polarized murine and human Th17 cells. NO also inhibits AHR expression in Th17 cells and the downstream events of AHR activation, including IL-22, IL-23 receptor, and Cyp1a1. Conversely, NO did not affect the polarization of Th17 cells from mice deficient in AHR. Furthermore, mice lacking inducible nitric oxide synthase (Nos2(-/-)) developed more severe experimental autoimmune encephalomyelitis than WT mice, with elevated AHR expression, increased IL-17A, and IL-22 synthesis. NO may therefore represent an important endogenous regulator to prevent overexpansion of Th17 cells and control of autoimmune diseases caused by environmental pollutants.

Topics: Animals; Autoimmune Diseases; Cell Proliferation; Cyclic GMP; Cytochrome P-450 CYP1A1; Humans; Inflammation; Interleukin-10; Interleukin-2; Interleukin-22; Interleukins; Ligands; Mice; Mice, Inbred BALB C; Models, Biological; Nitric Oxide; Nitric Oxide Synthase Type II; Proto-Oncogene Protein c-ets-1; Receptors, Interleukin; T-Lymphocytes, Helper-Inducer; Th17 Cells

The effect of carperitide, recombinant human atrial natriuretic peptide, on chronic heart failure (HF) has not been clarified. We investigated the beneficial effects of chronic carperitide treatment in rats with HF after experimental autoimmune myocarditis. A 28-day infusion of carperitide (n = 14) or vehicle (n = 14) was administrated to the rats 4 weeks after experimental autoimmune myocarditis induction. After 4 weeks, the myocardial levels of cyclic guanosine monophosphate (cGMP), left ventricular function, myocyte hypertrophy, interstitial fibrosis, myocardial capillary vessel density, and activity of one prominent substrate of cGMP, vasodilator-stimulated phosphoprotein (VASP) that may enhance angiogenesis, were measured. Carperitide treatment increased the myocardial levels of cGMP and attenuated the functional severity along with a decreased myocyte cross-sectional area, interstitial fibrosis, and an increased capillary to myocyte ratio. Furthermore, carperitide treatment enhanced the phosphorylation of VASP at Ser239, which was preferentially phosphorylated by cGMP-dependent protein kinase but not Ser157, which was preferentially phosphorylated by cyclic adenosine monophosphate-dependent protein kinase. Long-term carperitide treatment attenuates ventricular remodeling and ameliorates the progression of chronic HF. The effects of carperitide treatment are associated with increased neovascularization among the residual myocytes and an increase of VASP activation.

Topics: Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Capillaries; Cell Adhesion Molecules; Cell Size; Coronary Vessels; Cyclic GMP; Fibrosis; Heart Failure; Male; Microfilament Proteins; Myocarditis; Myocardium; Neovascularization, Physiologic; Phosphoproteins; Phosphorylation; Random Allocation; Rats; Rats, Inbred Lew; Recombinant Proteins; Stroke Volume; Ventricular Function, Left; Ventricular Remodeling

Effects of nitric oxide (NO) synthase inhibition on blood pressure and on the course of Heymann nephritis was examined in rats. L-NG-nitroarginine-methylester (L-NAME, 10 mg/100 ml in the drinking water for 12 weeks) was used as an inhibitor of NO synthase. Urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP), a second messenger of NO, was used as an indirect estimate of NO activity. Rats were divided into the following groups: control, nephritis, L-NAME, and nephritis-L-NAME. Urinary cGMP excretion was lower in the nephritis group (p < 0.05) and in the nephritis-L-NAME group (p < 0.005) compared with controls. Plasma atrial natriuretic peptide (ANP) levels were elevated in the nephritis (p < 0.001) and in the nephritis-L-NAME groups (p < 0.05. L-NAME treatment alone did not have any effect on plasma ANP levels. Blood pressure rose progressively in all L-NAME-treated rats. Most marked albuminuria developed in the nephritis-L-NAME group. No differences in the immunohistological findings were observed between the nephritis and the nephritis-L-NAME groups. NO synthase inhibition causes hypertension and aggravates albuminuria in chronic nephritis. Moreover, nephritis itself may decrease then production of cGMP either as a consequence of blunted NO activity or, in addition, because of ANP resistance. It appears that NO synthase inhibition does not change the immunological course of Heymann nephritis but rather the increased hemodynamic load makes the course of nephritis worse.

Topics: Albuminuria; Animals; Atrial Natriuretic Factor; Autoimmune Diseases; Blood Pressure; Complement C3; Cyclic GMP; Enzyme Inhibitors; Female; Glomerulonephritis; Immunoglobulin G; Immunohistochemistry; Kidney Glomerulus; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Renin; Time Factors

Evidence is presented showing that in experimental autoimmune myocarditis, there are certain components in IgG fraction of the sera that bind to myocardium muscarinic cholinergic receptors. The autoimmune IgG simulated the biologic effect of cholinergic agonists because (i) it increased cGMP levels, (ii) it decreased cAMP stimulated levels, and (iii) it reduced heart contractility and diminished reactivity to exogenous acetylcholine. Autoimmune IgG inhibited the binding of specific muscarinic cholinergic radioligand to purified myocardial membranes behaving as noncompetitive inhibitors. The recognition appears to be organ specific because the autoimmune IgG did not bind to muscarinic cholinergic receptors of urinary bladder. The presence of antibodies against antigens expressed in an accessible form to antibody in living myocardial cells might be related to some of the immunopathologic mechanisms participating in the pathogenesis of the experimental autoimmune myocarditis.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Binding, Competitive; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Electrocardiography; Fluorescent Antibody Technique; Heart; Immunoglobulin G; Mice; Mice, Inbred BALB C; Muscle Contraction; Myocarditis; Parasympathomimetics; Receptors, Muscarinic

Our current research program centers around the biologic and chemical characterization of the family of polypeptides present in thymosin fraction 5. A system of nomenclature has been developed and the peptides are being systematically isolated and chemically characterized. Thymosin fraction 5 and its component parts influence a variety of lymphocyte properties including cyclic nucleotide levels, migration inhibitory factor production, T-dependent antibody production, and expression of certain surface markers. Thymosin is being used in clinical trials to investigate its effects on immunodeficiency diseases, malignant diseases, and autoimmune diseases.

Topics: Animals; Autoimmune Diseases; Chemical Phenomena; Chemistry; Cyclic AMP; Cyclic GMP; Drug Evaluation; Guinea Pigs; Humans; Immunologic Deficiency Syndromes; In Vitro Techniques; Lymphocytes; Neoplasms; T-Lymphocytes; Thymosin; Thymus Hormones