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( Eun Ok Im ),( Charalabos Pothoulakis ),( Sang Hoon Rhee ) 대한소화기학회 2007 SIDDS Vol.9 No.-
Background/Aims: Emerging evidence supports an important beneficial role of probiotics in managing the intestinal homeostasis and inflammatory bowel disease (IBD). Bacillus polyfermenticus (BP) is non-pathogenic, Gram positive bacteria and known to produce a bactericidal factor(s) in human gastrointestinal tract. Here we investigated whether BP plays a probiotic effect in two pathophysiologically different models of mouse colitis. Methods: Mice were fed by gastric gavage with BP (107 CFU/day) for a week followed by BP plus DSS (4%) administration for additional two weeks. During the entire experimental period, pathophysiological signs of colitis (mortality, weight loss, diarrhea, and rectal bleeding) were monitored. Histopathology of colonic mucosa was examined to evaluate the severity of colitis. For TNBS-colitis model, mice were fed with oral gavage of BP for 1 week, followed by TNBS enema to induce colitis. Apoptosis in colonic mucosa was examined using TUNEL assay. Toll-like receptor (TLR) 2-or 4-deficient mice were used in DSS-colitis model to study the in vivo mechanism mediating the probiotic effect of BP. Results: Administration of BP substantially reduced mortality, weight loss, diarrhea, and rectal bleeding in DSS-colitis mice. Colon tissue sections from mice fed with this bacterium plus DSS showed more intact colonic mucosa, compared to the severe erosive lesions and massive leukocytes infiltration observed in colons of mice treated with DSS alone. Administration of BP reversed the histologic damages of colonic mucosa in TNBS-colitis. Moreover, administration of BP suppressed the apoptosis in colon from mice fed with DSS. In TLR2- or 4-deficient mice, however, administration of BP failed to relieve the patho-physiology of DSS-induced colitis. Conclusions: BP ameliorated the colonic inflammation and suppressed the apoptosis in colonic mucosa of experimental colitis, mediated through TLR2 or TLR4. These results suggest a potential application for Bacillus polyfer-menticus in IBD.
( Sang Hoon Rhee ),( Eun Ok Im ),( Charalabos Pothoulakis ) 대한소화기학회 2007 SIDDS Vol.9 No.-
Background/Aims: Host-commensal interaction by Toll-like receptors (TLRs) plays essential roles in the host. TLR5, specific receptor of flagellin, mediates pleiotropic intracellular responses in colonocytes. We aimed to investigate (1)whether host-microbial interaction by TLR5 modulates colon cancer and (2)the mechanism by which TLR5 regulates colon cancer. Methods: To generate TLR5- or MyD88-knocked down (KD) cells, colon cancer cells (DLD-1) were stably transfected with the siRNA vector to human TLR5 or MyD88, or the control vector. For mouse xenograft model of human colon cancer, we subcutaneously injected TLR5-KD, MyD88-KD, or its control cells into the flanks of nude mice (n=16/group), followed by measuring tumor growth. Tumors were excised from these mice and tumor histoputhology was examined. Tumors in nude mice were also treated with flagellin (5.0 mg/kg, one injection/every 2 days) and then we monitored the growth and histopathology of tumors. Using protein micro-array, we assessed the differential expression of cytokines in these tumors. To investigate the leukocytes infiltration into tumors, we performed immunohistochemistry with antibodies against neutrophil specific markers (Gr-1, 7/4) or macrophage-specific antigens (CD68, F4-80). Tumor angiogenesis was examined using antibody against PECAM-1, specific marker of vascular endothelial cell. Results: Lack of TLR5 or MyD88 expression dramatically enhanced tumor growth and inhibited tumor necrosis. TLR5 activation by flagellin substantially suppressed tumor growth and increased tumor necrosis. Tumors from TLR5- or MyD88-KD cells had reduced neutrophil attracting chemokines (ENA-78, MIP3a, and IL-8). Neutrophil infiltration was diminished in TLR5 or MyD88 deficient tumors, while tumor-associated macrophage infiltration or tumor angiogenesis was not changed in these tumors. Conclusions: TLR5 engagement by flagellin elicits potent anti-tumor activity, indicating an essential potent anti-tumor activity, indicating an essential role of host-commensal interaction by TLR5 in colon cancer.
Rhee, Sang Hoon,Ma, Elise L.,Lee, Yunna,Taché,, Yvette,Pothoulakis, Charalabos,Im, Eunok American Society for Biochemistry and Molecular Bi 2015 The Journal of biological chemistry Vol.290 No.43
<P>Colonic epithelium is the first line of defense against various pathological offenses in the gut. Previous studies have shown that the peptides of the corticotropin-releasing hormone (CRH) family modulate vascular endothelial growth factor (VEGF)-A production in other cells. Here we sought to investigate whether CRH and urocortin (Ucn) 3 regulate VEGF-A secretion in colonocytes through CRH receptors and to elucidate the underlying mechanism of action. CRH and Ucn 3 significantly increased the expression levels of VEGF-A mRNA and protein through CRH receptor 1 and 2, respectively, in human colonic epithelial cells and primary mouse intestinal epithelial cells. Underlying mechanisms involve activation of adenylyl cyclase with subsequent increase of intracellular cAMP level and increased DNA binding activity of transcription factor CREB on VEGF-A promoter region. Finally, genetic deficiency of CREB decreased intestinal inflammation and VEGF-A expression in a dextran sodium sulfate-induced colitis model. These results show that activation of CRH receptors by CRH ligands stimulates VEGF-A expression in intestinal epithelial cells through the cAMP/CREB pathway. Since VEGF-A boosts inflammatory responses through angiogenesis, these data suggest that CREB may be a key effector of CRH and Ucn 3-dependent inflammatory angiogenesis.</P>
Choo, Jieun,Lee, Yunna,Yan, Xin-jia,Noh, Tae Hwan,Kim, Seong Jin,Son, Sujin,Pothoulakis, Charalabos,Moon, Hyung Ryong,Jung, Jee H.,Im, Eunok American Society for Biochemistry and Molecular Bi 2015 The Journal of biological chemistry Vol.290 No.42
<P>Inflammatory bowel disease (IBD) is a chronic inflammatory disease with increasing incidence and prevalence worldwide. Here we investigated the newly synthesized jasmonate analogue 2-hydroxyethyl 5-chloro-4,5-didehydrojasmonate (J11-Cl) for its anti-inflammatory effects on intestinal inflammation. First, to test whether J11-Cl can activate peroxisome proliferator-activated receptors (PPARs), we performed docking simulations because J11-Cl has a structural similarity with anti-inflammatory 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), one of the endogenous ligands of PPAR gamma. J11-Cl bound to the ligand binding domain of PPAR gamma in the same manner as 15d-PGJ(2) and rosiglitazone, and significantly increased transcriptional activity of PPAR gamma. In animal experiments, colitis was significantly reduced in mice with J11-Cl treatment, determined by analyses of survival rate, body weight changes, clinical symptoms, and histological evaluation. Moreover, J11-Cl decreased production of pro-inflammatory cytokines including IL-6, IL-8, and G-CSF as well as chemokines including chemokine (C-C motif) ligand (CCL) 20, chemokine (C-X-C motif) ligand (CXCL) 2, CXCL3, and chemokine (C-X3-C motif) ligand 1 (CX3CL1) in colon tissues, and LPS or TNF-alpha-stimulated macrophages and epithelial cells. In contrast, production of anti-inflammatory cytokines including IL-2 and IL-4 as well as the proliferative factor, GM-CSF, was increased by J11-Cl. Furthermore, inhibition of MAPKs and NF-kappa B activation by J11-Cl was also observed. J11-Cl reduced intestinal inflammation by increasing the transcriptional activity of PPAR gamma and modulating inflammatory signaling pathways. Therefore, our study suggests that J11-Cl may serve as a novel therapeutic agent against IBD.</P>
Kim, Dae Hong,Hwang, Jae Sam,Lee, Ik Hwan,Nam, Seung Taek,Hong, Ji,Zhang, Peng,Lu, Li Fang,Lee, Junguee,Seok, Heon,Pothoulakis, Charalabos,Lamont, John Thomas,Kim, Ho American Society for Biochemistry and Molecular Bi 2016 The Journal of biological chemistry Vol.291 No.7
<P>The epithelial cells of the gut form a physical barrier against the luminal contents. The collapse of this barrier causes inflammation, and its therapeutic restoration can protect the gut against inflammation. EGF enhances mucosal barrier function and increases colonocyte proliferation, thereby ameliorating inflammatory responses in the gut. Based on our previous finding that the insect peptide CopA3 promotes neuronal growth, we herein tested whether CopA3 could increase the cell proliferation of colonocytes, enhance mucosal barrier function, and ameliorate gut inflammation. Our results revealed that CopA3 significantly increased epithelial cell proliferation in mouse colonic crypts and also enhanced colonic epithelial barrier function. Moreover, CopA3 treatment ameliorated Clostridium difficile toxin As-induced inflammation responses in the mouse small intestine (acute enteritis) and completely blocked inflammatory responses and subsequent lethality in the dextran sulfate sodium-induced mouse model of chronic colitis. The marked CopA3-induced increase of colonocyte proliferation was found to require rapid protein degradation of p21(Cip1/Waf1), and an in vitro ubiquitination assay revealed that CopA3 directly facilitated ubiquitin ligase activity against p21(Cip1/Waf1). Taken together, our findings indicate that the insect peptide CopA3 prevents gut inflammation by increasing epithelial cell proliferation and mucosal barrier function.</P>