Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-γ and TNF-α production

2001 ◽  
Vol 281 (4) ◽  
pp. R1264-R1273 ◽  
Author(s):  
Britta Siegmund ◽  
Giamila Fantuzzi ◽  
Florian Rieder ◽  
Fabia Gamboni-Robertson ◽  
Hans-Anton Lehr ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Intestinal Inflammation ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Suppressive Effect ◽  
Confocal Laser ◽  
Colon Tissue ◽  
Lamina Propria Mononuclear Cells ◽  
Ifn Γ

Interleukin (IL)-18, initially described as interferon (IFN)-γ-inducing factor, is expressed in the inflamed mucosa of patients with Crohn's disease. To investigate the role of IL-18 in intestinal inflammation, the effect of neutralizing antimurine IL-18 antiserum in dextran sulfate sodium (DSS)-induced colitis in BALB/c and C57BL/6 mice was examined. During a dose response of DSS, levels of colonic IL-18 increased parallel with clinical worsening. With the use of confocal laser microscopy, the increased IL-18 was localized to the intestinal epithelial layer. Anti-IL-18 treatment resulted in a dose-dependent reduction of the severity of colitis in both BALB/c and C57BL/6 mice. Colon shortening following DSS-induced colitis was partially prevented in the treatment groups. In the colon tissue homogenates, IFN-γ concentrations were lower in the anti-IL-18-treated DSS-fed mice compared with untreated DSS-fed mice. This suppressive effect of anti-IL-18 administered in vivo was also observed on spontaneous tumor necrosis factor-α, IL-18, and IFN-γ production from ex vivo colon organ cultures. The stimulation of lamina propria mononuclear cells by IL-18 and IL-12 resulted in a synergistic increase in IFN-γ synthesis. These findings suggest that IL-18 is a pivotal mediator in experimental colitis.

scholarly journals Antibiotic-associated dysbiosis affects the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in experimental colitis models

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Francesco Strati ◽  
Meritxell Pujolassos ◽  
Claudia Burrello ◽  
Maria Rita Giuffrè ◽  
Georgia Lattanzi ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Lamina Propria ◽  
Mononuclear Cells ◽  
Intestinal Inflammation ◽  
Fecal Microbiota Transplantation ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Fecal Microbiota ◽  
Inkt Cells ◽  
Lamina Propria Mononuclear Cells

Abstract Background The gut microbiota plays a central role in host physiology and in several pathological mechanisms in humans. Antibiotics compromise the composition and functions of the gut microbiota inducing long-lasting detrimental effects on the host. Recent studies suggest that the efficacy of different clinical therapies depends on the action of the gut microbiota. Here, we investigated how different antibiotic treatments affect the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in an experimental colitis model and in ex vivo experiments with human intestinal biopsies. Results Murine fecal donors were pre-treated with different antibiotics, i.e., vancomycin, streptomycin, and metronidazole before FMT administration to colitic animals. The analysis of the gut microbiome, fecal metabolome, and the immunophenotyping of colonic lamina propria immune cells revealed that antibiotic pre-treatment significantly influences the capability of the microbiota to control intestinal inflammation. Streptomycin and vancomycin-treated microbiota failed to control intestinal inflammation and were characterized by the blooming of pathobionts previously associated with IBD as well as with metabolites related to the presence of oxidative stress and metabolism of simple sugars. On the contrary, the metronidazole-treated microbiota retained its ability to control inflammation co-occurring with the enrichment of Lactobacillus and of innate immune responses involving iNKT cells. Furthermore, ex vivo cultures of human intestinal lamina propria mononuclear cells and iNKT cell clones from IBD patients with vancomycin pre-treated sterile fecal water showed a Th1/Th17 skewing in CD4+ T-cell populations; metronidazole, on the other hand, induced the polarization of iNKT cells toward the production of IL10. Conclusions Diverse antibiotic regimens affect the ability of the gut microbiota to control intestinal inflammation in experimental colitis by altering the microbial community structure and microbiota-derived metabolites.

scholarly journals OP32 Mincle signalling promotes intestinal mucosal inflammation through induction of macrophage pyroptosis and neutrophil chemotaxis in Crohn’s disease

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S031-S031
Author(s):  
W GONG ◽  
K Guo ◽  
J Ren
Keyword(s):  
Intestinal Inflammation ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Mitogen Activated Protein Kinase ◽  
Mucosal Inflammation ◽  
Neutrophil Chemotaxis ◽  
Knock Out ◽  
Mitogen Activated Protein ◽  
Proinflammatory Role

Abstract Background Macrophage-inducible C-type lectin (Mincle) signalling plays a proinflammatory role in different organs such as the brain and liver, but its role in intestinal inflammation remains unknown. Methods We studied the characteristics of Mincle signalling expression in CD patients and experimental colitis. The functional role of Mincle signalling in the intestine was addressed in experimental colitis models in vivo by using mice with Mincle knock out (Mincle−/−), neutralising anti-Mincle antibody, Mincle pharmacologic agonist and RNA-seq genome expression analysis. Bone marrow-derived macrophages were collected from mice and used to further verify the effect of Mincle signalling in macrophages. Results Mincle signalling was significantly elevated in active human CD and experimental colitis, and macrophages were the principal leukocyte subset that up-regulates Mincle signalling. Mincle deficiency ameliorated the colitis by reducing induced macrophage pyroptosis (Figure 1), whereas activation of Mincle with the pharmacologic agonist worsened the intestinal inflammation (Figure 2). Moreover, the ex vivo studies confirmed that Mincle signalling activation promoted and its absence restricted release of proinflammatory cytokines from pyroptosis of macrophage (Figure 3). Finally, Mincle/Syk signalling could promote the production of chemokines to recruit neutrophils by activating Mitogen-Activated Protein Kinase (MAPK) during inflammation (Figure 4). Conclusion Mincle signalling promotes intestinal mucosal inflammation through induction of macrophage pyroptosis and neutrophil chemotaxis. Modulation of the Mincle/Syk axis emerges as a potential therapeutic strategy to target inflammation and treat CD.

scholarly journals Sustained suppression of IL-18 by employing a vaccine ameliorates intestinal inflammation in TNBS-induced murine colitis

2019 ◽  
Vol 5 (7) ◽  
pp. FSO405 ◽  
Author(s):  
Qingdong Guan ◽  
Richard Warrington ◽  
Sem Moreno ◽  
Gefei Qing ◽  
Carolyn Weiss ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Trinitrobenzene Sulfonic Acid ◽  
Colon Tissue ◽  
Murine Colitis ◽  
Virus Like Particle ◽  
Cytokine Levels ◽  
Ifn Γ ◽  
In Vivo Effects

Aim: To develop IL-18 peptide-based virus-like particle vaccines that elicit autoantibodies against IL-18 and to evaluate the in vivo effects of the vaccines in murine colitis. Methods: Recombinant IL-18 vaccines were constructed, and the effects of the vaccines were evaluated in trinitrobenzene sulfonic acid-induced acute and chronic colitis in mice. Results: Two murine IL-18 peptide-based vaccines (A and D) were developed, which induced relative long-lasting specific antibodies against IL-18. Vaccine-immunized mouse antisera could partially block IL-18-induced IFN-γ production in vitro. Mice receiving vaccine D, not vaccine A, had a significant decrease in intestinal inflammation, collagen deposition and pro-inflammatory cytokine levels in colon tissue. Conclusion: IL-18 vaccine may provide a potential therapeutic approach in the treatment of Crohn’s disease.

scholarly journals IFN-γ and IL-17A regulate intestinal crypt production of CXCL10 in the healthy and inflamed colon

2020 ◽  
Vol 318 (3) ◽  
pp. G479-G489 ◽  
Author(s):  
Travis Walrath ◽  
Robert A. Malizia ◽  
Xinjun Zhu ◽  
Stephen P. Sharp ◽  
Shanti S. D'Souza ◽  
...  
Keyword(s):  
Intestinal Inflammation ◽  
Ex Vivo ◽  
Colonic Crypt ◽  
Intestinal Crypt ◽  
Colon Crypt ◽  
Crypt Epithelium ◽  
Negative Effect ◽  
Cytokine Milieu ◽  
Ifn Γ

During intestinal inflammation, immature cells within the intestinal crypt are called upon to replenish lost epithelial cell populations, promote tissue regeneration, and restore barrier integrity. Inflammatory mediators including TH1/TH17-associated cytokines influence tissue health and regenerative processes, yet how these cytokines directly influence the colon crypt epithelium and whether the crypt remains responsive to these cytokines during active damage and repair, remain unclear. Here, using laser-capture microdissection and primary colon organoid culture, we show that the cytokine milieu regulates the ability of the colonic crypt epithelium to participate in proinflammatory signaling. IFN-γ induces the TH1-recruiting, proinflammatory chemokine CXCL10/IP10 in primary murine intestinal crypt epithelium. CXCL10 was also induced in colonic organoids derived from mice with active, experimentally induced colitis, suggesting that the crypt can actively secrete CXCL10 in select cytokine environments during colitis. Colon expression of cxcl10 further increased during infectious and noninfectious colitis in Il17a−/− mice, demonstrating that IL-17A exerts a negative effect on CXCL10 in vivo. Furthermore, IL-17A directly antagonized CXCL10 production in ex vivo organoid cultures derived from healthy murine colons. Interestingly, direct antagonism of CXCL10 was not observed in organoids derived from colitic mouse colons bearing active lesions. These data, highlighting the complex interplay between the cytokine milieu and crypt epithelia, demonstrate proinflammatory chemokines can be induced within the colonic crypt and suggest the crypt remains responsive to cytokine modulation during inflammation. NEW & NOTEWORTHY Upon damage, the intestinal epithelium regenerates to restore barrier function. Here we observe that the local colonic cytokine milieu controls the production of procolitic chemokines within the crypt base and colon crypts remain responsive to cytokines during inflammation. IFN-γ promotes, while IL-17 antagonizes, CXCL10 production in healthy colonic crypts, while responses to cytokines differ in inflamed colon epithelium. These data reveal novel insight into colon crypt responses and inflammation-relevant alterations in signaling.

Mincle/Syk Signalling Promotes Intestinal Mucosal Inflammation Through Induction of Macrophage Pyroptosis in Crohn’s Disease

2020 ◽  
Vol 14 (12) ◽  
pp. 1734-1747
Author(s):  
Wenbin Gong ◽  
Tao Zheng ◽  
Kun Guo ◽  
Miao Fang ◽  
Haohao Xie ◽  
...  
Keyword(s):  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Proinflammatory Cytokines ◽  
Intestinal Inflammation ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Mitogen Activated Protein Kinase ◽  
Mucosal Inflammation ◽  
Knock Out

Abstract Background Macrophage-inducible C-type lectin [Mincle] signalling plays a proinflammatory role in different organs such as the brain and liver, but its role in intestinal inflammation, including Crohn’s disease [CD], remains unknown. Methods The characteristics of Mincle signalling expression in CD patients and experimental colitis were examined. The functional role of Mincle signalling in the intestine was addressed in experimental colitis models in vivo by using Mincle knock-out [Mincle-/-] mice. In addition, neutralising anti-Mincle antibody, downstream spleen tyrosine kinase [Syk] inhibitor, and Mincle pharmacological agonist were used to study the Mincle signalling in intestine. Bone marrow-derived macrophages were collected from mice and used to further verify the effect of Mincle signalling in macrophages. Results This study has shown that Mincle signalling was significantly elevated in active human CD and experimental colitis, and macrophages were the principal leukocyte subset that upregulate Mincle signalling. Mincle deficiency and Syk pharmacological inhibition ameliorated the colitis by reducing induced macrophage pyroptosis, and activation of Mincle with the agonist aggravated the intestinal inflammation. The ex vivo studies demonstrated that activation of Mincle signalling promoted the release of proinflammatory cytokines, whereas its absence restricted release of proinflammatory cytokines from pyroptosis of macrophages. In addition, Mincle/Syk signalling in macrophages could promote the production of chemokines to recruit neutrophils by activating mitogen-activated protein kinase [MAPK] during intestinal inflammation. Conclusions Mincle signalling promotes intestinal mucosal inflammation by inducing macrophage pyroptosis. Modulation of the Mincle/Syk axis emerges as a potential therapeutic strategy to target inflammation and treat CD.

HG-9-91-01 Attenuates Murine Experimental Colitis by Promoting Interleukin-10 Production in Colonic Macrophages Through the SIK/CRTC3 Pathway

2021 ◽  
Author(s):  
Yong Fu ◽  
Gailing Ma ◽  
Yuqian Zhang ◽  
Wenli Wang ◽  
Tongguo Shi ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Experimental Colitis ◽  
Underlying Mechanism ◽  
Interleukin 10 ◽  
Camp Response Element Binding ◽  
Cellular Level ◽  
Trinitrobenzene Sulfonic Acid ◽  
Murine Colitis ◽  
Anti Inflammatory

Abstract Background Interleukin-10 (IL-10) is a potent immunoregulatory cytokine that plays a pivotal role in maintaining mucosal immune homeostasis. As a novel synthetic inhibitor of salt-inducible kinases (SIKs), HG-9-91-01 can effectively enhance IL-10 secretion at the cellular level, but its in vivo immunoregulatory effects remain unclear. In this study, we investigated the effects and underlying mechanism of HG-9-91-01 in murine colitis models. Methods The anti-inflammatory effects of HG-9-91-01 were evaluated on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-, dextran sulfate sodium–induced colitis mice, and IL-10 knockout chronic colitis mice. The in vivo effector cell of HG-9-91-01 was identified by fluorescence-activated cell sorting and quantitative real-time polymerase chain reaction. The underlying mechanism of HG-9-91-01 was investigated via overexpressing SIKs in ANA-1 macrophages and TNBS colitis mice. Results Treatment with HG-9-91-01 showed favorable anticolitis effects in both TNBS- and DSS-treated mice through significantly promoting IL-10 expression in colonic macrophages but failed to protect against IL-10 KO murine colitis. Further study indicated that HG-9-91-01 markedly enhanced the nuclear level of cAMP response element-binding protein (CREB)-regulated transcription coactivator 3 (CRTC3), whereas treatment with lentiviruses encoding SIK protein markedly decreased the nuclear CRTC3 level in HG-9-91-01–treated ANA-1 macrophages. In addition, intracolonic administration with lentiviruses encoding SIK protein significantly decreased the nuclear CRTC3 level in the lamina propria mononuclear cells and ended the anti-inflammatory activities of HG-9-91-01. Conclusions We found that HG-9-91-01 promoted the IL-10 expression of colonic macrophages and exhibited its anticolitis activity through the SIK/CRTC3 axis, and thus it may represent a promising strategy for inflammatory bowel disease therapy.

scholarly journals The therapeutic efficacy of mesenchymal stromal cells on experimental colitis was improved by the IFN-γ and poly(I:C) priming through promoting the expression of indoleamine 2,3-dioxygenase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ji-Young Lim ◽  
Byung-Su Kim ◽  
Da-Bin Ryu ◽  
Tae Woo Kim ◽  
Gyeongsin Park ◽  
...  
Keyword(s):  
Weight Loss ◽  
Disease Activity ◽  
Stromal Cells ◽  
Therapeutic Efficacy ◽  
Activity Index ◽  
Disease Activity Index ◽  
Experimental Colitis ◽  
Poly I:C ◽  
Colon Tissue ◽  
Ifn Γ

Abstract Background Inflammatory bowel disease is a chronic and excessive inflammation of the colon and small intestine. We previously reported that priming of mesenchymal stromal cells (MSCs) with poly(I:C) induced them to express indoleamine 2,3-dioxygenase (IDO). We tried to find out whether the IFN-γ and poly(I:C)-primed MSCs have better therapeutic efficacy on the experimental colitis in the IDO1-dependent manner. Methods To compare the therapeutic effects between the unstimulated MSCs and primed MSCs on murine colitis, mice (C57BL6) were administered with 2.5% dextran sodium sulfate (DSS) in drinking water for 5 days and injected with MSCs intraperitoneally on days 1 and 3 following DSS ingestion. The disease activity index score and body weight loss were assessed daily until day 9. Results Mice receiving the IFN-γ and poly(I:C)-primed MSCs showed a reduced disease activity index and less weight loss. Colon tissue from the same mice presented attenuated pathological damage, increased Paneth cells, increased IDO1-expressing cells, and better proliferation of enterocytes. The primed MSC treatment upregulated the mRNA expression of intestinal stem cell markers (Lgr5, Olfm4, and Bmi1), enterocyte differentiation markers (Muc2, Alpi, Chga, and occludin), and regulatory T (Treg) cells (Foxp3). The same treatment decreased inflammatory cell infiltration to lymphoid organs and the level of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, and MCP-1) in colon tissue. Notably, in vivo pharmacologic inhibition of the IDO1 activity blocked the Foxp3 upregulation in colon tissue and diminished the protective effects of the primed MSC. Conclusions The priming of MSCs with the IFN-γ and poly(I:C) is a promising new strategy to improve the therapeutic efficacy of MSC and is worth further research.

scholarly journals Interleukin-7-Dependent Production of RANTES That Correlates with Human Immunodeficiency Virus Disease Progression

2003 ◽  
Vol 77 (7) ◽  
pp. 4389-4395 ◽  
Author(s):  
Anuska Llano ◽  
Jordi Barretina ◽  
Arantxa Gutiérrez ◽  
Bonaventura Clotet ◽  
José A. Esté
Keyword(s):  
Human Immunodeficiency Virus ◽  
Disease Progression ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Virus Disease ◽  
Chemokine Production ◽  
Interleukin 7 ◽  
Cell Counts ◽  
Immunodeficiency Virus

ABSTRACT There is a relationship between CD4-T-cell number and circulating interleukin 7 (IL-7) levels in human immunodeficiency virus (HIV)-positive individuals. Here, we show that IL-7 induced a dose-dependent production of CCL3 (MIP-1α), CCL4 (MIP-1β), and CCL5 (RANTES) in peripheral blood mononuclear cells (PBMC), ex vivo tonsil lymphoid tissue of HIV− individuals, and PBMC from HIV+ individuals, suggesting that IL-7 may regulate β-chemokine production in vivo. In a cross-sectional study of HIV+ individuals (n = 130), a weak but significant correlation between IL-7 and RANTES was noted (r = 0.379; P < 0.001). Remarkably, the correlation between IL-7 and RANTES increased to an r value of 0.798 (P < 0.001) if individuals with low CD4 cell counts (<200 cells/μl) were excluded from the analysis. Our results suggest that there is a relationship between IL-7 and the production of RANTES both in vitro and in vivo that is lost in immune-compromised patients (CD4 count of <200 cells/μl) but that could be restored by antiretroviral therapy. Unlike the case for IL-7, high levels of RANTES suggest an intermediate stage of HIV disease progression.

scholarly journals Local Immune Responses to Chlamydia pneumoniae in the Lungs of BALB/c Mice during Primary Infection and Reinfection

1998 ◽  
Vol 66 (11) ◽  
pp. 5113-5118 ◽  
Author(s):  
Jenni M. Penttilä ◽  
Marjukka Anttila ◽  
Mirja Puolakkainen ◽  
Aino Laurila ◽  
Kari Varkila ◽  
...  
Keyword(s):  
Primary Infection ◽  
Bacterial Infections ◽  
Chlamydia Pneumoniae ◽  
Mononuclear Cells ◽  
Relative Increase ◽  
Culturable Bacteria ◽  
Ifn Γ ◽  
Tissue Reactions

ABSTRACT Cell-mediated immune (CMI) responses play a major role in protection as well as pathogenesis of many intracellular bacterial infections. In this study, we evaluated the infection kinetics and assessed histologically the lymphoid reactions and local, in vitro-restimulated CMI responses in lungs of BALB/c mice, during both primary infection and reinfection with Chlamydia pneumoniae. The primary challenge resulted in a self-restricted infection with elimination of culturable bacteria by day 27 after challenge. A mild lymphoid reaction characterized the pathology in the lungs. In vitro CMI responses consisted of a weak proliferative response and no secretion of gamma interferon (IFN-γ). The number of lung-derived mononuclear cells increased substantially during the primary infection; the largest relative increase was observed in B cells (B220+). After reinfection, the number of lung-derived mononuclear cells increased further, and the response consisted mainly of T cells. The reinfection was characterized in vivo by significant protection from infection (fewer cultivable bacteria in the lungs for a shorter period of time) but increased local lymphoid reaction at the infection site. In vitro, as opposed to the response in naive mice, acquired immunity was characterized by a strongly Th1-biased (IFN-γ) CMI response. These results suggest that repeated infections with C. pneumoniae may induce Th1-type responses with similar associated tissue reactions, as shown in C. trachomatis infection models.

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