Immune Protection of a Helminth Protein in the DSS-Induced Colitis Model in Mice

Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, and it has the potential to diminish the quality of life. Recent clinical and experimental evidence demonstrate protective aspects of parasitic helminth infection against IBD. Reports have highlighted the potential use of helminths and their byproducts as potential treatment for IBD. In the current study, we studied the effect of a newborn larvae-specific serine protease from Trichinella spiralis (TsSp) on the host immune and inflammatory responses. A 49-kDa recombinant TsSp (rTsSp) was expressed in Escherichia coli BL21 (DE3) and purified. The cytotoxicity of rTsSp was analyzed. The immune protective effect of rTsSp was studied by using dextran sodium sulfate (DSS)-induced mouse colitis model. The result illustrated that rTsSp has no toxic effects on cells. We further demonstrated that administration of the rTsSp without the additional adjuvant before the induction of DSS-induced colitis reduced the severity of intestinal inflammation and the disease index; it suppressed macrophage infiltration, reduced TNF-α secretion, and induced IL-10 expression. Our findings suggest therapeutic potential of rTsSp on colitis by altering the effect of macrophages. Data also suggest immunotherapy with rTsSp holds promise for use as an additional strategy to positively modulate inflammatory processes involved in IBD.

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Mucosa-associated microbiota drives pathogenic functions in IBD-derived intestinal iNKT cells

Life Science Alliance ◽

10.26508/lsa.201800229 ◽

2019 ◽

Vol 2 (1) ◽

pp. e201800229 ◽

Cited By ~ 6

Author(s):

Claudia Burrello ◽

Gabriella Pellegrino ◽

Maria Rita Giuffrè ◽

Giulia Lovati ◽

Ilaria Magagna ◽

...

Keyword(s):

Lamina Propria ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Ex Vivo ◽

Lymphoid Tissues ◽

Inkt Cells ◽

Inflammatory Processes ◽

Inflammatory Bowel

Inflammatory bowel disease (IBD) pathogenesis has been linked to the aberrant activation of the Gut-associated lymphoid tissues against components of the intestinal microbiota. Although the contribution of CD4+ T helper cells to inflammatory processes is being increasingly acknowledged, the functional engagement of human invariant natural killer T (iNKT) cells is still poorly defined. Here, we evaluated the functional characteristics of intestinal iNKT cells during IBD pathogenesis and to exploit the role of mucosa-associated microbiota recognition in triggering iNKT cells’ pro-inflammatory responses in vivo. Lamina propria iNKT cells, isolated from surgical specimens of active ulcerative colitis and Crohn’s disease patients and non-IBD donors, were phenotypically and functionally analyzed ex vivo, and stable cell lines and clones were generated for in vitro functional assays. iNKT cells expressing a pro-inflammatory cytokine profile were enriched in the lamina propria of IBD patients, and their exposure to the mucosa-associated microbiota drives pro-inflammatory activation, inducing direct pathogenic activities against the epithelial barrier integrity. These observations suggest that iNKT cell pro-inflammatory functions may contribute to the fuelling of intestinal inflammation in IBD patients.

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In Vitro Evaluation of the Anti-Inflammatory Effect of KMUP-1 and in Vivo Analysis of Its Therapeutic Potential in Osteoarthritis

Biomedicines ◽

10.3390/biomedicines9060615 ◽

2021 ◽

Vol 9 (6) ◽

pp. 615

Author(s):

Shang-En Huang ◽

Erna Sulistyowati ◽

Yu-Ying Chao ◽

Bin-Nan Wu ◽

Zen-Kong Dai ◽

...

Keyword(s):

Articular Cartilage ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Antioxidant Properties ◽

Serum Levels ◽

Gene Expressions ◽

Tnf Α ◽

Anti Inflammatory

Osteoarthritis is a degenerative arthropathy that is mainly characterized by dysregulation of inflammatory responses. KMUP-1, a derived chemical synthetic of xanthine, has been shown to have anti-inflammatory and antioxidant properties. Here, we aimed to investigate the in vitro anti-inflammatory and in vivo anti-osteoarthritis effects of KMUP-1. Protein and gene expressions of inflammation markers were determined by ELISA, Western blotting and microarray, respectively. RAW264.7 mouse macrophages were cultured and pretreated with KMUP-1 (1, 5, 10 μM). The productions of TNF-α, IL-6, MMP-2 and MMP- 9 were reduced by KMUP-1 pretreatment in LPS-induced inflammation of RAW264.7 cells. The expressions of iNOS, TNF-α, COX-2, MMP-2 and MMP-9 were also inhibited by KMUP-1 pretreatment. The gene expression levels of TNF and COX families were also downregulated. In addition, KMUP-1 suppressed the activations of ERK, JNK and p38 as well as phosphorylation of IκBα/NF-κB signaling pathways. Furthermore, SIRT1 inhibitor attenuated the inhibitory effect of KMUP-1 in LPS-induced NF-κB activation. In vivo study showed that KMUP-1 reduced mechanical hyperalgesia in monoiodoacetic acid (MIA)-induced rats OA. Additionally, KMUP-1 pretreatment reduced the serum levels of TNF-α and IL-6 in MIA-injected rats. Moreover, macroscopic and histological observation showed that KMUP-1 reduced articular cartilage erosion in rats. Our results demonstrated that KMUP-1 inhibited the inflammatory responses and restored SIRT1 in vitro, alleviated joint-related pain and cartilage destruction in vivo. Taken together, KMUP-1 has the potential to improve MIA-induced articular cartilage degradation by inhibiting the levels and expression of inflammatory mediators suggesting that KMUP-1 might be a potential therapeutic agent for OA.

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Physiological Basis for Novel Drug Therapies Used to Treat the Inflammatory Bowel Diseases I. Immunology and therapeutic potential of antiadhesion molecule therapy in inflammatory bowel disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00423.2004 ◽

2005 ◽

Vol 288 (2) ◽

pp. G169-G174 ◽

Cited By ~ 56

Author(s):

Gert Van Assche ◽

Paul Rutgeerts

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Adhesion Molecules ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Therapeutic Potential ◽

Physiological Basis ◽

Inflammatory Bowel

Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. They are also involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. In intestinal inflammation, many adhesion molecules are upregulated, but α4-integrins most likely hold a key position in directing leukocytes into the inflamed bowel wall. Therapeutic compounds directed against trafficking of leukocytes have been designed and are being developed as a novel class of drugs in the treatment of Crohn's disease and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Second, the changes in adhesion molecules and T cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered with respect to the therapeutic potential and the safety of antiadhesion molecule treatment. Antegren, or natalizumab, a humanized anti-α4 integrin IgG4 antibody, has been most extensively evaluated and may be close to registration. A more specific humanized α4β7-integrin MLN-02 has shown preliminary clinical efficacy in ulcerative colitis, and both antergren and MLN-02 appear to be very safe. Trials with the anti-ICAM-1 antisense oligonucleotide ISIS-2302 in steroid refractory Crohn's disease have provided conflicting efficacy data. In the near future, some of these novel biological agents may prove valuable therapeutic tools in the management of refractory inflammatory bowel disease, although it is too early to define the patient population that will benefit most from these agents.

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Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms

Mediators of Inflammation ◽

10.1080/09511920410001713529 ◽

2004 ◽

Vol 13 (3) ◽

pp. 181-187 ◽

Cited By ~ 45

Author(s):

Joanna Balding ◽

Wendy J. Livingstone ◽

Judith Conroy ◽

Lesley Mynett-Johnson ◽

Donald G. Weir ◽

...

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Disease Incidence ◽

Strong Association ◽

Tnf Α ◽

Genes Encoding ◽

Inflammatory Processes ◽

Inflammatory Bowel ◽

Cytokine Gene Polymorphisms

THE mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n=172) and healthy controls (n=389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-α-308 polymorphism (p=0.0135). There was also variation in the frequency of IL-6-174 and TNF-α-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p=0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.

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Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

Pharmaceutics ◽

10.3390/pharmaceutics12060539 ◽

2020 ◽

Vol 12 (6) ◽

pp. 539

Author(s):

Bahez Gareb ◽

Antonius T. Otten ◽

Henderik W. Frijlink ◽

Gerard Dijkstra ◽

Jos G. W. Kosterink

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Genetically Modified Organisms ◽

Intestinal Inflammation ◽

Systemic Exposure ◽

Tnf Α ◽

Inflammatory Bowel ◽

Factor Α ◽

Necrosis Factor

Crohn’s disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) characterized by intestinal inflammation. Increased intestinal levels of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) are associated with disease activity and severity. Anti-TNF-α therapy is administered systemically and efficacious in the treatment of IBD. However, systemic exposure is associated with adverse events that may impede therapeutic treatment. Clinical studies show that the efficacy correlates with immunological effects localized in the gastrointestinal tract (GIT) as opposed to systemic effects. These data suggest that site-specific TNF-α inhibition in IBD may be efficacious with fewer expected side effects related to systemic exposure. We therefore reviewed the available literature that investigated the efficacy or feasibility of local TNF-α inhibition in IBD. A literature search was performed on PubMed with given search terms and strategy. Of 8739 hits, 48 citations were included in this review. These studies ranged from animal studies to randomized placebo-controlled clinical trials. In these studies, local anti-TNF-α therapy was achieved with antibodies, antisense oligonucleotides (ASO), small interfering RNA (siRNA), microRNA (miRNA) and genetically modified organisms. This narrative review summarizes and discusses these approaches in view of the clinical relevance of local TNF-α inhibition in IBD.

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Chronic colitis-induced visceral pain is associated with increased anxiety during quiescent phase

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00248.2018 ◽

2019 ◽

Vol 316 (6) ◽

pp. G692-G700 ◽

Cited By ~ 6

Author(s):

Emmeline Salameh ◽

Mathieu Meleine ◽

Guillaume Gourcerol ◽

Jean-Claude do Rego ◽

Jean-Luc do Rego ◽

...

Keyword(s):

Intestinal Inflammation ◽

Visceral Pain ◽

Myeloperoxidase Activity ◽

Therapeutic Approaches ◽

Chronic Colitis ◽

Functional Symptoms ◽

Tnf Α ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Novel Therapeutic

Inflammatory bowel diseases (IBD) are characterized by repetition of flares and remission periods leading to chronic postinflammatory sequelae. Among postinflammatory sequelae, one-third of patients with IBD are suffering from functional symptoms or psychological comorbidities that persist during remission. The aim of our study was to assess functional and behavioral sequelae of chronic colitis in rats with quiescent intestinal inflammation. Chronic colitis was induced by a weekly intrarectal injection of increasing concentrations of trinitrobenzene sulfonic acid (TNBS) for 3 wk (15–45 mg of TNBS) in 30 rats, whereas the control rats ( n = 24) received the vehicle. At 50 days post-TNBS, visceral sensitivity was assessed by visceromotor response to colorectal distension, and transient receptor potential vanilloid type 1 (TRPV1) expression was also quantified in the colon and dorsal root ganglia. Barrier function and inflammatory response were assessed by studying intestinal permeability, tight junction protein, myeloperoxidase activity, histological score, and cytokine production (IL-6, IL-10, and TNF-α). Anxiety behavioral tests were performed from 50 to 64 days after the last TNBS injection. Chronic TNBS induced 1) a visceral hypersensitivity ( P = 0.03), 2) an increased colon weight-to-length ratio ( P = 0.01), 3) higher inflammatory and fibrosis scores ( P = 0.0390 and P = 0.0016, respectively), and 4) a higher colonic IL-6 and IL-10 production ( P = 0.008 and P = 0.005, respectively) compared with control rats. Intestinal permeability, colonic production of TNF-α, myeloperoxidase activity, and TRPV1 expression did not differ among groups. Chronic TNBS increased anxiety-related behavior in the open-field test and in the acoustic stress test. In conclusion, chronic colitis induced functional sequelae such as visceral hypersensitivity and increased anxiety with a low-grade intestinal inflammation. Development of a representative animal model will allow defining novel therapeutic approaches to achieve a better management of IBD-related sequelae.NEW & NOTEWORTHY Patients with inflammatory bowel diseases have impaired quality of life. Therapeutic progress to control mucosal inflammation provides us an opportunity to develop novel approaches to understand mechanisms behind postinflammatory sequelae. We used a chronic colitis model to study long-term sequelae on visceral pain, gut barrier function, and psychological impact. Chronic colitis induced functional symptoms and increased anxiety in the remission period. It might define novel therapeutic approaches to achieve a better inflammatory bowel disease-related sequelae management.

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Phosphatase Shp2 exacerbates intestinal inflammation by disrupting macrophage responsiveness to interleukin-10

Journal of Experimental Medicine ◽

10.1084/jem.20181198 ◽

2019 ◽

Vol 216 (2) ◽

pp. 337-349 ◽

Cited By ~ 10

Author(s):

Peng Xiao ◽

Huilun Zhang ◽

Yu Zhang ◽

Mingzhu Zheng ◽

Rongbei Liu ◽

...

Keyword(s):

Intestinal Inflammation ◽

Interleukin 10 ◽

Blood Monocytes ◽

Stat3 Signaling ◽

Tnf Α ◽

Mouse Macrophages ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

Further Development

Inflammatory cytokines produced by activated macrophages largely contribute to the pathological signs of inflammatory bowel disease (IBD). Interleukin-10 (IL-10) is the predominant anti-inflammatory cytokine in the intestine, and its therapeutic efficacy for IBD has been clinically tested. Nevertheless, how the function of IL-10 is regulated in the intestinal microenvironment remains unknown, which largely hinders the further development of IL-10–based therapeutic strategies. Here, we found that the expression of phosphatase Shp2 was increased in colonic macrophages and blood monocytes from IBD patients compared with those from healthy controls. Shp2 deficiency in macrophages protects mice from colitis and colitis-driven colon cancer. Mechanistically, Shp2 disrupts IL-10–STAT3 signaling and its dependent anti-inflammatory response in human and mouse macrophages. Furthermore, a Shp2-inducing role of TNF-α is unveiled in our study. Collectively, our work identifies Shp2 as a detrimental factor for intestinal immune homeostasis and hopefully will be helpful in the future exploitation of IL-10 immunotherapy for IBD.

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Epithelial Sel1L is required for the maintenance of intestinal homeostasis

Molecular Biology of the Cell ◽

10.1091/mbc.e15-10-0724 ◽

2016 ◽

Vol 27 (3) ◽

pp. 483-490 ◽

Cited By ~ 19

Author(s):

Shengyi Sun ◽

Rohan Lourie ◽

Sara B. Cohen ◽

Yewei Ji ◽

Julia K. Goodrich ◽

...

Keyword(s):

Small Intestine ◽

Cell Biology ◽

Intestinal Inflammation ◽

Laboratory Mice ◽

Associated Lesions ◽

Inflammatory Bowel ◽

Idiopathic Disease ◽

Increased Susceptibility

Inflammatory bowel disease (IBD) is an incurable chronic idiopathic disease that drastically decreases quality of life. Endoplasmic reticulum (ER)–associated degradation (ERAD) is responsible for the clearance of misfolded proteins; however, its role in disease pathogenesis remains largely unexplored. Here we show that the expression of SEL1L and HRD1, the most conserved branch of mammalian ERAD, is significantly reduced in ileal Crohn’s disease (CD). Consistent with this observation, laboratory mice with enterocyte-specific Sel1L deficiency (Sel1LΔIEC) develop spontaneous enteritis and have increased susceptibility to Toxoplasma gondii–induced ileitis. This is associated with profound defects in Paneth cells and a disproportionate increase of Ruminococcus gnavus, a mucolytic bacterium with known association with CD. Surprisingly, whereas both ER stress sensor IRE1α and effector CHOP are activated in the small intestine of Sel1LΔIEC mice, they are not solely responsible for ERAD deficiency–associated lesions seen in the small intestine. Thus our study points to a constitutive role of Sel1L-Hrd1 ERAD in epithelial cell biology and the pathogenesis of intestinal inflammation in CD.

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Studies on the Interleukin-10 Gene in Animal Models of Colitis

Canadian Journal of Gastroenterology ◽

10.1155/2001/303729 ◽

2001 ◽

Vol 15 (8) ◽

pp. 557-558

Author(s):

Hugh J Freeman

Keyword(s):

Inflammatory Bowel Disease ◽

Animal Models ◽

Bowel Disease ◽

Inflammatory Process ◽

Intestinal Inflammation ◽

Therapeutic Potential ◽

Interleukin 10 ◽

Necrosis Factor Alpha ◽

Inflammatory Bowel ◽

Deficient Mice

Cytokines play a role in the inflammatory process in colitis and may have therapeutic potential. Interleukin-10 (IL-10) has both immunomodulatory and anti-inflammatory properties. IL-10-deficient mice develop intestinal inflammation with increased tissue levels of other cytokines, including tumour necrosis factor-alpha. In patients with inflammatory bowel disease, impaired IL-10 production by lamina propria T cells occurs and human recombinant IL-10 improves clinical parameters in inflammatory bowel disease (eg, Crohn's disease). There seem to be conflicting results in differing animal models, and the timing of administration of IL-10 relative to onset of colitis may be critical, possibly due to rapid clearance of IL-10. Interestingly, in IL-10 gene-deficient mice raised in germ-free conditions, the intestinal inflammatory changes normally observed in conventional nongerm-free conditions are not detected, suggesting a role for luminal bacteria in the pathogenesis of the inflammatory process.

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Fidaxomicin and OP-1118 Inhibit Clostridium difficile Toxin A- and B-Mediated Inflammatory Responses via Inhibition of NF-κB Activity

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01513-17 ◽

2017 ◽

Vol 62 (1) ◽

Cited By ~ 1

Author(s):

Hon Wai Koon ◽

Jiani Wang ◽

Caroline C. Mussatto ◽

Christina Ortiz ◽

Elaine C. Lee ◽

...

Keyword(s):

Clostridium Difficile ◽

Intestinal Inflammation ◽

Inflammatory Responses ◽

Human Colon ◽

Toxin A ◽

Primary Metabolite ◽

Necrosis Factor Alpha ◽

Toxin B ◽

Content Type ◽

Tnf Α

ABSTRACTClostridium difficilecauses diarrhea and colitis by releasing toxin A and toxin B. In the human colon, both toxins cause intestinal inflammation and stimulate tumor necrosis factor alpha (TNF-α) expression via the activation of NF-κB. It is well established that the macrolide antibiotic fidaxomicin is associated with reduced relapses ofC. difficileinfection. We showed that fidaxomicin and its primary metabolite OP-1118 significantly inhibited toxin A-mediated intestinal inflammation in micein vivoand toxin A-induced cell roundingin vitro. We aim to determine whether fidaxomicin and OP-1118 possess anti-inflammatory effects against toxin A and toxin B in the human colon and examine the mechanism of this response. We used fresh human colonic explants, NCM460 human colonic epithelial cells, and RAW264.7 mouse macrophages to study the mechanism of the activity of fidaxomicin and OP-1118 against toxin A- and B-mediated cytokine expression and apoptosis. Fidaxomicin and OP-1118 dose-dependently inhibited toxin A- and B-induced TNF-α and interleukin-1β (IL-1β) mRNA expression and histological damage in human colonic explants. Fidaxomicin and OP-1118 inhibited toxin A-mediated NF-κB phosphorylation in human and mouse intestinal mucosae. Fidaxomicin and OP-1118 also inhibited toxin A-mediated NF-κB phosphorylation and TNF-α expression in macrophages, which was reversed by the NF-κB activator phorbol myristate acetate (PMA). Fidaxomicin and OP-1118 prevented toxin A- and B-mediated apoptosis in NCM460 cells, which was reversed by the addition of PMA. PMA reversed the cytoprotective effect of fidaxomicin and OP-1118 in toxin-exposed human colonic explants. Fidaxomicin and OP-1118 inhibitC. difficiletoxin A- and B-mediated inflammatory responses, NF-κB phosphorylation, and tissue damage in the human colon.

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