| Inflammatory bowel disease (IBD) is a chronic inflammatory disease of intestinal,including Crohn’s disease (CD) and ulcerative colitis (UC). The etiology of IBD is stillunclear, but environmental factors in the intestinal lumen and inappropriate host immuneresponses in genetically predisposed individuals are involved. Dysfunctions of the intestinalimmune system and cross-reactivity against host epithelial cells have been implicated asmajor mechanisms by which inflammation occurs. During acute inflammatory episodes, themucosal lining of the intestine displays a characteristic inflammatory infiltrate of mast cells,lymphocytes, macrophages, and activated neutrophils. An excessive Th1response toantigenic stimulus leads to increased levels of various cytokines, the most crucial of whichare IL-1, IL-6, TNF-α, IFN-γ, IL-12, and IL-18. Although the initial purpose of theinflammatory response is to provide protection against the invasion of foreign antigens, inIBD, the immune response becomes dysregulated, resulting in damage to host intestinaltissue. The expression of pro-inflammatory cytokines in the intestinal mucosa from IBDpatients is markedly enhanced, highlighting the polarization of T-cell activity that ischaracteristic of the defective inflammatory response.Neuro-endocrine-immuno-regulatory network is a complex and extensive regulatorynetwork formed by the nervous, endocrine and immune which regulates various biologicalprocesses. Brain gut peptide is an important information molecule in neuro-endocrine-immuno-regulatory network which plays an important role in regulating visceral sensory,immunity and secretion. Opioid peptides are brain gut peptides which involved in the body’simmune regulation by binding to receptors. At present, we have found and cloned three kindsof opioid receptors, namely μ-opioid receptors (MOR), κ-opioid receptors (KOR) andδ-opioid receptor (DOR).MOR, a member of the G protein-linked receptor superfamily, is expressed in varioustissues including the gut, particularly on lymphocytes and myenteric and submucosal plexi.Activation of MOR by endogenous or exogenous agonists has a pleiotropic action onimmune and physiological processes. To investigate the changes and role of MOR in rats, mRNA levels of MOR in different tissues and peripheral blood lymphocytes were detectedby realtime PCR and the concentration of β-endorphin and dynorphin in the serum andcerebrospinal fluid were measured by ELISA at different times after induction by TNBS;mouse peritoneal macrophages were isolated and cultured, the mRNA levels of iNOS, IL-6,TNF-α in macrophages were detected by realtime PCR and the concentration of TNF-α andIL-6in cell supernatants were measured by ELISA after incubated with MOR ligands in thepresence or absence of LPS treatment; the effects of MOR ligands on the TEER and tightjunction proteins expression were quantified against the response to TNF-α in a cellularmodel of the intestinal epithelium using Caco-2cells.Our results showed that the high mRNA levels of MOR were detected in the rathypothalamus, thymus and peripheral blood lymphocytes in the pathogenesis of IBD, and thelowest mRNA level of MOR was detected in the colon tissue. Remarkably, MOR changedmarkedly during day3to7after induction by TNBS. Conversely, with the recovery ofenteropathy and alleviation of symptoms, their mRNA levels began to change and graduallytrended towards normal levels. Moreover, the protein levels of endogenous ligand dynorphinand β-endorphin in serum and cerebrospinal fluid were significantly reduced at thepathogenesis of IBD. MOR activation significantly reduced LPS-induced mRNA levels ofiNOS, IL-6and TNF-α in mouse peritoneal macrophages and protein levels of IL-6andTNF-α in cell supernatants. In addition, MOR activation significantly attenuatedTNF-α-induced reduction in transepithelial electrical resistance and mRNA levels of tightjunction proteins in Caco-2cell. |
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