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8Summarizing Discussion Neuropeptide receptor expression in inflammatory bowel disease Beek, W.P. ter Citation Beek, W. P. ter. (2008, April 3). Neuropeptide receptor expression in inflammatory bowel disease. Retrieved from https://hdl.handle.net/1887/12667 Version: Corrected Publisher’s Version Licence agreement concerning inclusion of doctoral thesis in the License: Institutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/12667 Note: To cite this publication please use the final published version (if applicable). Summarizing Discussion 8 120 - Chapter eight Neuropeptides Neuropeptides are signalling peptides that are produced by neural, endocrine and/or immune cells. They exert their effects by binding to G protein-coupled receptors on the target cells where they act as neurotransmitters, paracrine regulators or systemic hormones. These neuropeptides are involved in different human neoplastic and non-neoplastic diseases. For instance, the receptors for somatostatin, gastrin-releasing peptide and substance P are overexpressed in neuroendocrine tumours [1], prostatic carcinomas [2] and rheumatoid arthritis [3] respectively. With the use of radiolabelled peptides these receptors can be applied to in vivo scintigraphy or peptide radiotherapy. These and other neuropeptides, with their receptors, have been suggested to be involved in the pathology of inflammatory bowel disease (IBD), a chronic inflammatory disease of the gastrointestinal tract that is characterized by changes in motility, pain and diarrhoea. Based on clinical-histological and macroscopic features IBD is divided into two entities: Crohn’s disease and ulcerative colitis. Chapter One of this thesis gives an overview of the role of neuropeptides in the inflammatory process in general and in IBD in particular. The molecules are secreted by nerves of the enteric nervous system and endocrine cells in the mucosa which are both in close proximity to inflammatory cells in the mucosa. These immune cells have receptors for several neuropeptides on their surfaces and a subgroup of these immune cells is itself capable of secreting neuropeptides. Further, the neuropeptides are involved in the regulation of the motility of the intestine and in chloride secretion. The involvement of neuropeptides in the inflammatory response, motility and chloride secretion, three processes that are impaired in IBD, suggests a role for these neuropeptides in the pathology of IBD. Furthermore, there may be a therapeutic and/or diagnostic application for these neuropeptides or their antagonists in IBD. However, before interventions can be made, it is important to obtain more knowledge about the status of the receptors of these neuropeptides in tissue of IBD patients. Chapter two gives an outline of the various studies performed in thesis. Summarizing Discusion - 121 Techniques In recent years molecular techniques have become increasingly important in receptor research, but it should be kept in mind that mRNA levels do not necessarily correlate with the number of receptors expressed in the examined tissue. An example of this discrepancy between mRNA levels and receptor expression is shown in chapter three. Although autoradiographic binding studies did show an increase of the substance P receptor expression in mucosa of IBD patients, there was no increase in the amount of mRNA in the same tissue. Although molecular techniques also have specific advantages (sensitive, fast, information of the different receptor types), they do not provide information about receptor affinity, specificity and selectivity. Therefore, and for reasons of quantification of receptor protein, radioligand binding studies are still necessary. Even better is a combination of molecular and binding techniques, with additional immunohistochemistry for information about the precise location of the receptors. This will give a complete picture of the neuropeptide receptor status in the tested tissue. Substance P Substance P belongs to the family of mammalian tachykinins and is present in the enteric nervous system, where it is an important mediator of neurogenic inflammation. However, the peptide also exerts other pro-inflammatory functions [4]. In chapter three the expression of the substance P receptor was studied in patients with IBD using the three above-mentioned techniques. Other studies have already shown the results of one or two techniques, but this is the first time that three complementary techniques describe the receptor status in the same tissue. Autoradiography showed that the number of substance P binding sites in the mucosa of IBD patients was higher (55 compared to 18 fmol/g in control patients) but that the amount of mRNA was not increased. Immunohistochemistry showed that the increased substance P binding to the mucosa of IBD patients is not due to expression of the receptor at new locations, but rather to an increase in the number 122 - Chapter eight of receptors at the normal locations. Further, our data suggest that this increase in substance P receptor expression level is due to an internal pool of receptors or early synthesis of new receptors as the mRNA content is not increased in the inflamed intestine of IBD patients. As a consequence of the increased substance P receptor expression an increased inflammatory activity will probably be seen in response to substance P. Therefore NK-1 receptor antagonist are expected to decrease the substance P mediated immune cell activity, ion secretion, intestinal permeability and colonic motility. Highly selective antagonists for the NK-1 receptor are currently in use in rheumatoid arthritis, depression and anxiety, but the potential beneficial effects of these antagonists in IBD first have to be shown by controlled clinical studies. Neurotensin Another neuropeptide receptor studied in this thesis is the receptor for neurotensin, a 13 amino-acid peptide located in the entire gastrointestinal tract, with the highest concentration in the ileum [5]. Neurotensin is involved in several processes in the gastrointestinal tract such as chloride secretion [6], motility [7] and inflammation [8]. Neurotensin acts via three different receptors with the neurotensin receptor-1 being the most important in the gastrointestinal tract [9]. We studied the receptor status of this neuropeptide in IBD and control tissue with the three techniques described above. In chapter four the results of storage phosphor autoradiography are given and in chapter five a differentiation is made between the various receptor types for neurotensin and the additional PCR and immunohistochemistry data are presented. Autoradiography showed neurotensin binding to colonic and ileal smooth muscle with binding in the colon being higher than in the ileum. Also the mucosa showed neurotensin binding, but the expression level was very low. Further, we found that in the smooth muscle of inflamed tissue of patients with IBD fewer receptors were expressed compared to the non-inflamed regions. In chapter five cold saturation studies showed that this expression was due to neurotensin receptor-1 and -3. No neurotensin receptor-2 was found. RT-PCR showed mRNA of the neurotensin receptor-1 and -3 being present in the human intestine. The Summarizing Discusion - 123 mRNA levels of neurotensin receptor-1 and -3 were lower in the inflamed smooth muscle of IBD patients, as was the neurotensin binding described in chapter four. Immunohistochemistry showed no changes in the location of the receptors. The decreased binding sites for neurotensin in IBD suggest that the receptor normally has a beneficial effect on inflammatory status of the intestine. This is confirmed by a mice DSS model where administration of a neurotensin receptor-1 antagonist worsened the inflammatory response and injection of neurotensin had a healing effect [10]. Gastrin releasing peptide The third group of neuropeptide of interest to us was the family of bombesin-like peptides and their receptors. This peptide family has several functions in the gastrointestinal tract, such as the stimulation of endocrine and exocrine secretion, the involvement in smooth muscle contraction, and the regulation of immunological processes [11-13]. Gastrin-releasing peptide and neuromedin B are two members of this family that are present in humans [14]. There are three receptors described for the bombesin-like peptides [15-17] and in chapter six we showed that in the human intestine only the gastrin-releasing peptide receptor is expressed. This receptor was most prominently present in the longitudinal muscle (including the myenteric plexus) of the colon and to a lesser degree also in the circular smooth muscle of colon and ileum. However, in the mucosa the gastrin-releasing peptide receptor was only found in low quantities in the colon, but not in the ileum. In patients with Crohn’s disease the expression of the gastrin-releasing peptide receptor was less in the colonic smooth muscle. In patients having ulcerative colitis this was not the case. The difference in gastrin-releasing peptide receptor expression between patients with Crohn’s disease and ulcerative colitis makes this receptor a possible target to distinguish between the two diseases. Further the decrease of the receptors in Crohn’s disease may have a protective effect in these patients on the enhanced motility. 124 - Chapter eight Motilin In chapter seven we described studies on the expression of the motilin receptor. Motilin is a gastrointestinal peptide mainly known for its function in phase III of the
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