Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC). It is thought to be caused by genetic, abnormal immune response of the intestinal immune system and dysfunction of intestinal mucosal barrier against enteric bacteria. Mutational genes can affect the development of IBDs via certain signaling pathways. The abnormal signaling pathways play an important role in the inflammatory process and can lead to dysregulation of the inflammatory response and are crucial in the pathogenesis of IBDs. The signaling pathways mainly include P38 MAPK, JNK MAPK, PI3K/Akt, NF-kappaB signaling pathways. Intestinal microorganisms play a key role in the initiation and maintenance of disease. Disorders of signaling pathways including TLR, NF-kappaB can act on the intestinal barrier, and cause uninhibitedly release of effector T cells which are the central cells mediating inflammation in CD. This review highlights relevant patents and a new insight of signaling pathways associated with IBDs will help to develop better therapeutic approaches.
Background Macrophages can be polarized into pro-inflammatory (M1) and anti-inflammatory (M2) subtypes. However, whether macrophage polarization plays a role in necrotizing enterocolitis (NEC) remains unknown. Materials and methods Macrophages were derived from the THP-1 human monocyte cell line. Apoptosis of human fetal small intestinal epithelial FHs-74 cells was determined by Annexin V/PI flow cytometry and by Western blotting to detect cleaved caspase-3. The effect of heparin-binding EGF-like growth factor (HB-EGF) on macrophage polarization was determined by flow cytometry with M1/ M2 markers and real time PCR. In vivo, experimental NEC was induced in mouse pups by repeated exposure to hypoxia, hypothermia and hypertonic feedings. Intestinal histologic sections were subjected to immunohistochemical staining for the detection of M1 and M2 macrophages. Results In vitro, FHs-74 cell apoptosis was increased after co-culture with macrophages and LPS. This apoptosis was increased by exposure to M1 conditioned medium (CM) and suppressed by exposure to M2 CM. HB-EGF significantly decreased LPS-induced M1 polarization and promoted M2 polarization via STAT3 activation. Addition of HB-EGF to LPS-stimulated macrophages suppressed the pro-apoptotic effects of the macrophages on FHs-74 cells. In vivo, we found enhanced intestinal macrophage infiltration in pups subjected to NEC, the majority of which were M1 macrophages. HB-EGF treatment of pups subjected to experimental NEC significantly reduced M1 and increased M2 polarization, and protected the intestines from NEC. Conclusions M1 macrophages promote NEC by increasing intestinal epithelial apoptosis. HB-EGF protects the intestines from NEC by preventing M1 and promoting M2 polarization.
BackgroundNecrotizing enterocolitis (NEC) is associated with loss of neurons and glial cells in the enteric nervous system (ENS). Our goal was to determine whether enteric neural stem cell (NSC) transplantation, in conjunction with heparin binding-epidermal growth factor-like growth factor (HB-EGF), could protect against experimental NEC.MethodsIn vitro, HB-EGF effect on NSC proliferation and migration, and the receptors utilized by HB-EGF to exert these effects, were determined. In vivo, mouse pups were exposed to experimental NEC and treated with either NSC alone, HB-EGF alone, NSC+HB-EGF, or HB-EGF over-expressing NSC. NSC engraftment and differentiation into neurons in the ENS, intestinal injury, intestinal permeability and intestinal motility were determined.ResultsHB-EGF promotes NSC proliferation via ErbB-1 receptors and enhances NSC migration via ErbB-1, ErbB-4 and Nardilysin receptors. HB-EGF significantly enhanced the engraftment of transplanted NSC into the ENS during NEC. NSC transplantation significantly reduced NEC incidence and improved gut barrier function and intestinal motility, and these effects were augmented by simultaneous administration of HB-EGF or by transplantation of HB-EGF-over-expressing NSC.ConclusionsHB-EGF promotes NSC proliferation and migration. HB-EGF and NSC reduce intestinal injury and improve gut barrier function and intestinal motility in experimental NEC. Combined HB-EGF and NSC transplantation may represent a potential future therapy to prevent NEC.
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