neuropeptide-y and Inflammatory-Bowel-Diseases

Inflammatory bowel disease (IBD) is a chronic recurrent condition whose etiology is unknown, and it includes ulcerative colitis, Crohn's disease, and microscopic colitis. These three diseases differ in clinical manifestations, courses, and prognoses. IBD reduces the patients' quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal (GI) neuroendocrine peptides/amines (NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover, the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD, and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin, the neuropeptide Y family, and substance P are proinflammatory, while the chromogranin/secretogranin family, vasoactive intestinal peptide, somatostatin, and ghrelin are anti-inflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD, and are candidate targets for treatments of this disease.

Topics: Amines; Animals; Chromogranins; Disease Models, Animal; Gastrointestinal Microbiome; Gastrointestinal Tract; Ghrelin; Humans; Inflammatory Bowel Diseases; Neuroendocrine Cells; Neuropeptide Y; Neurosecretory Systems; Prevalence; Quality of Life; Recurrence; Serotonin; Serotonin Antagonists; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Inflammatory bowel disease (IBD) includes three main disorders: ulcerative colitis, Crohn's disease, and microscopic colitis. The etiology of IBD is unknown and the current treatments are not completely satisfactory. Interactions between the gut neurohormones and the immune system are thought to play a pivot role in inflammation, especially in IBD. These neurohormones are believed to include members of the neuropeptide YY (NPY) family, which comprises NPY, peptide YY (PYY), and pancreatic polypeptide (PP). Understanding the role of these peptides may shed light on the pathophysiology of IBD and potentially yield an effective treatment tool. Intestinal NPY, PYY, and PP are abnormal in both patients with IBD and animal models of human IBD. The abnormality in NPY appears to be primarily caused by an interaction between immune cells and the NPY neurons in the enteric nervous system; the abnormalities in PYY and PP appear to be secondary to the changes caused by the abnormalities in other gut neurohormonal peptides/amines that occur during inflammation. NPY is the member of the NPY family that can be targeted in order to decrease the inflammation present in IBD.

Topics: Animals; Gastrointestinal Hormones; Humans; Immune System; Inflammatory Bowel Diseases; Neurons; Neuropeptide Y; Pancreatic Polypeptide

Enteroendocrine cells (EEC) produce neuropeptides, which are crucially involved in the maintenance of the intestinal barrier. Hence, EEC dysfunction is suggested to be involved in the complex pathophysiology of inflammatory bowel disease (IBD), which is characterized by decreased intestinal barrier function. However, the underlying mechanisms for EEC dysfunction are not clear and suitable models for a better understanding are lacking. Here, we demonstrate that Carboxypeptidase E (CPE) is specifically expressed in EEC of the murine colon and ileum and that its deficiency is associated with reduced intestinal levels of Neuropeptide Y (NPY) and Peptide YY (PYY), which are both produced by EEC. Moreover, cpe-/- mice exhibit an aggravated course of DSS-induced chronic colitis compared to wildtype littermates. In addition, we observed elevated mucosal IL-6 and KC transcript levels already at baseline conditions in cpe-/- mice. Moreover, supernatants obtained from isolated intestinal crypts of cpe-/- mice lead to increased IL-6 and KC expression in MODE-K cells in the presence of LPS. This effect was reversible by co-administration of recombinant NPY, suggesting a CPE mediated immunosuppressive effect in the intestines by influencing the processing of specific neuropeptides. In this context, the chemotaxis of bone marrow derived macrophages towards respective supernatants was enhanced. In conclusion, our data point to an anti-inflammatory role of CPE in the intestine by influencing local cytokine levels and thus regulating the migration of myeloid immune cells into the mucosa. These findings highlight the importance of EEC for intestinal homeostasis and propose EEC as potential therapeutic targets in IBD.

Topics: Animals; Carboxypeptidase H; Cell Movement; Cells, Cultured; Chromogranin B; Colitis; Colon; Dextran Sulfate; Homeostasis; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Mice, Inbred C57BL; Myeloid Cells; Neuropeptide Y; Protein Transport

Neurogenic inflammation plays a major role in the pathogenesis of inflammatory bowel disease (IBD). We examined the role of neuropeptide Y (NPY) and neuronal nitric oxide synthase (nNOS) in modulating colitis.. Colitis was induced by administration of dextran sodium sulphate (3% DSS) or streptomycin pre-treated Salmonella typhimurium (S.T.) in wild type (WT) and NPY (NPY(-/-)) knockout mice. Colitis was assessed by clinical score, histological score and myeloperoxidase activity. NPY and nNOS expression was assessed by immunostaining. Oxidative stress was assessed by measuring catalase activity, glutathione and nitrite levels. Colonic motility was assessed by isometric muscle recording in WT and DSS-treated mice.. DSS/S.T. induced an increase in enteric neuronal NPY and nNOS expression in WT mice. WT mice were more susceptible to inflammation compared to NPY(-/-) as indicated by higher clinical & histological scores, and myeloperoxidase (MPO) activity (p<0.01). DSS-WT mice had increased nitrite, decreased glutathione (GSH) levels and increased catalase activity indicating more oxidative stress. The lower histological scores, MPO and chemokine KC in S.T.-treated nNOS(-/-) and NPY(-/-)/nNOS(-/-) mice supported the finding that loss of NPY-induced nNOS attenuated inflammation. The inflammation resulted in chronic impairment of colonic motility in DSS-WT mice. NPY -treated rat enteric neurons in vitro exhibited increased nitrite and TNF-alpha production.. NPY mediated increase in nNOS is a determinant of oxidative stress and subsequent inflammation. Our study highlights the role of neuronal NPY and nNOS as mediators of inflammatory processes in IBD.

Topics: Animals; Catalase; Colitis; Dextran Sulfate; Disease Models, Animal; Gene Deletion; Glutathione; Inflammation; Inflammatory Bowel Diseases; Mice; Mice, Knockout; Neuropeptide Y; Nitric Oxide Synthase Type I; Nitrites; Oxidative Stress; Peroxidase

In inflammatory diseases such as Crohn's disease (CD) and ulcerative colitis (UC), one would expect that TNF or IL-6 stimulates the hypothalamus, which activates the hypothalamus-autonomic nervous system (HANS) axis and the hypothalamic-pituitary-adrenal (HPA) axis in a parallel fashion. The study was initiated in order to investigate the parallelism of the HANS and HPA axes. We measured a typical marker of the HANS axis (neuropeptide Y, NPY) and of the HPA axis (serum cortisol). Plasma NPY was positively correlated with serum cortisol in control subjects (R(Rank)=0.259, p=0.026), which is a sign for the parallel activation of the two axes in healthy subjects. However, serum cortisol was not correlated with plasma NPY in CD or UC patients. In the active CD or UC, inclusion of patients with and without prior prednisolone therapy revealed a negative correlation between the serum cortisol and plasma NPY (CD: R(Rank)=-0.285, p<0.05; UC: R(Rank)=-0.510, p<0.01). This study demonstrates that the two stress axes seem to act in a parallel fashion in control subjects but are uncoupled in IBD patients. Uncoupling of these two axes may be partly due to prior corticosteroid therapy, whereas inverse coupling is a result of simultaneous corticosteroid therapy. It is discussed how the uncoupling of the two anti-inflammatory stress axes can appear.

Topics: Adult; Anti-Inflammatory Agents; Female; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Inflammatory Bowel Diseases; Interleukin-6; Male; Middle Aged; Neuroimmunomodulation; Neuropeptide Y; Pituitary-Adrenal System; Prednisolone; Sex Factors; Sympathetic Nervous System; Tumor Necrosis Factor-alpha

P-selectin, a membrane glycoprotein which is expressed on activated platelets and endothelial cells, plays a crucial role in the inflammatory response. The main action is adhesion of leukocytes, facilitation of diapedesis and induction of cytokine production from monocytes (MCP-1 and IL-8), mediated via RANTES released from activated platelets. An abnormal platelet activity has been reported in patients with ulcerative colitis (UC) and Crohn's disease (CD), jointly referred to as inflammatory bowel disease (IBD), which could have an aggravating influence on the inflammatory response. In addition, an up-regulation of platelet IL-8 receptors among patients with IBD has been reported. To reveal a presumptuous platelet dysfunction we analysed the expression of platelet surface P-selectin at resting state and after stimulation with thrombin, collagen, epinephrine and interleukin 8 (IL-8), and plasma levels of soluble P-selectin, neuropeptide Y (NPY) and RANTES in patients with IBD.. Blood from twelve healthy subjects (control group) and twenty-one patients with IBD who had not taken any anti-platelet drugs or steroids were analysed.. Patients were sub-grouped according to disease entity, disease activity and 5ASA medication. Surface P-selectin expression on isolated human platelets and plasma P-selectin, NPY and RANTES were analysed with ELISA. All values are presented as mean +/- standard error of the mean (SEM). Mann-Whitney U test and Wilcoxon matched rank test were used for statistical analyses.. Patients with IBD in remission (n = 9) had higher basal P-selectin expression, 0.38+/-0.04, compared to the control group (n = 12), 0.22+/-0.03,p < 0.01. UC patients (n = 16) showed down-regulation of P-selectin expression after stimulation with IL-8, 0.26+/-0.03 to 0.22+/-0.02, p < 0.05. No significant differences could be observed concerning soluble P-selectin and NPY in plasma. Patients with 5ASA (n = 12) had lower levels of plasma RANTES, 2.39+/-0.06 microg/l, compared to the control group (n = 12), 3.29+/-0.19 microg/l, p < 0.01, and patients without 5ASA (n = 9), 2.90+/-0.17 microg/l, p < 0.05.. Patients with IBD in remission have higher basal platelet surface P-selectin expression. An exaggerated platelet activity with increased expression of platelet P-selectin and release of inflammatory mediators such as RANTES, which is chemotactic and induce chemokine production, could have a reinforcing and aggravating influence on the inflammatory response and increase the susceptibility to IBD. In addition IL-8 has a down-regulating effect on platelet surface P-selectin expression and 5ASA medication seems to lower plasma RANTES. If 5ASA is responsible for lowering the concentration of RANTES this could be one of the beneficial outcomes of 5ASA medication.

Topics: Adult; Aged; Antigens, CD; Aspirin; Blood Platelets; Chemokine CCL5; Female; Humans; Inflammatory Bowel Diseases; Integrin beta3; Interleukin-8; Male; Middle Aged; Neuropeptide Y; P-Selectin; Platelet Membrane Glycoproteins