transforming-growth-factor-beta and Rodent-Diseases

Irritable bowel syndrome (IBS) is a functional bowel disorder (FBD).. To assess the therapeutic effects of paeoniflorin (PF) on IBS in rats.. Sixty male Sprague-Dawley rats were randomly divided into normal, model, positive drug, low-dose PF, medium-dose PF and high-dose PF groups (n = 10). After gavage for 2 consecutive weeks, the effect of PF on abdominal pain symptoms was assessed based on the abdominal withdrawal reflex (AWR) score, fecal water content and pathological changes in colon tissues. D-lactate, interleukin-1β (IL-1β), transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay, and phosphorylated nuclear factor kappa B (p-NF-κB) p65 was detected by Western blotting. The abundance and diversity changes of intestinal flora were explored using 16S ribosomal RNA sequencing.. In PF groups, the mucosal morphology of colon tissues was intact, and the glands were arranged neatly and structured clearly, without obvious inflammatory cell infiltration. Compared with the model group, PF groups had significantly elevated pain threshold, and mRNA and protein levels of zonula occludens-1 (ZO-1) and occludin, decreased AWR score at 20 mmHg pressure, fecal water content, mRNA levels of IL-1β, TGF-β, and TNF-α, protein level of p-NF-κB p65 and level of serum D-lactate, and reduced levels of serum IL-1β, TGF-β, and TNF-α (. PF exerts therapeutic effects on IBS in rats probably by regulating the intestinal flora, and then up-regulating the expressions of ZO-1 and occludin in colon tissue while down-regulating the levels of IL-1β, TGF-β, TNF-α, D-lactate and p-NF-κB p65.

Topics: Animals; Irritable Bowel Syndrome; Lactates; Male; NF-kappa B; Occludin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Rodent Diseases; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Previous studies showed that Trichinella spiralis galectin (Tsgal) facilitates larval invasion of intestinal epithelium cells (IECs). However, IEC proteins binding with Tsgal were not identified, and the mechanism by which Tsgal promotes larval invasion is not clear. Toll-like receptors (TLRs) are protein receptors responsible for recognition of pathogens. The aim of this study was to investigate whether recombinant Tsgal (rTsgal) binds to TLR-4, activates inflammatory pathway in gut epithelium and mediates T. spiralis invasion. Indirect immunofluorescence (IIF), GST pull-down and co-immunoprecipitation (Co-IP) assays confirmed specific binding between rTsgal and TLR-4 in Caco-2 cells. qPCR and Western blotting showed that binding of rTsgal with TLR-4 up-regulated the TLR-4 transcription and expression in Caco-2 cells, and activated p-NF-κB p65 and p-ERK1/2. Activation of inflammatory pathway TLR-4/MAPK-NF-κB by rTsgal up-regulated pro-inflammatory cytokines (IL-1β and IL-6) and down-regulated anti-inflammatory cytokine TGF-β in Caco-2 cells, and induced intestinal inflammation. TAK-242 (TLR-4 inhibitor) and PDTC (NF-κB inhibitor) significantly inhibited the activation of TLR-4 and MAPK-NF-κB pathway. Moreover, the two inhibitors also inhibited IL-1β and IL-6 expression, and increased TGF-β expression in Caco-2 cells. In T. spiralis infected mice, the two inhibitors also inhibited the activation of TLR-4/MAPK-NF-κB pathway, ameliorated intestinal inflammation, impeded larval invasion of gut mucosa and reduced intestinal adult burdens. The results showed that rTsgal binding to TLR-4 in gut epithelium activated MAPK-NF-κB signaling pathway, induced the expression of TLR-4 and pro-inflammatory cytokines, and mediated larval invasion. Tsgal might be regarded as a candidate molecular target of vaccine against T. spiralis enteral invasive stage.

Topics: Animals; Caco-2 Cells; Cytokines; Galectins; Humans; Inflammation; Interleukin-6; Intestinal Mucosa; Larva; Mice; NF-kappa B; Rodent Diseases; Toll-Like Receptor 4; Transforming Growth Factor beta; Trichinella spiralis

Rapid innate responses to viral encounters are crucial to shaping the outcome of infection, from viral clearance to persistence. Transforming growth factor β (TGF-β) is a potent immune suppressor that is upregulated early upon viral infection and maintained during chronic infections in both mice and humans. However, the role of TGF-β signaling in regulating individual cell types in vivo is still unclear. Using infections with two different persistent viruses, murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV; Cl13), in their natural rodent host, we observed that TGF-β signaling on dendritic cells (DCs) did not dampen DC maturation or cytokine production in the early stages of chronic infection with either virus in vivo. In contrast, TGF-β signaling prior to (but not during) chronic viral infection directly restricted the natural killer (NK) cell number and effector function. This restriction likely compromised both the early control of and host survival upon MCMV infection but not the long-term control of LCMV infection. These data highlight the context and timing of TGF-β signaling on different innate cells that contribute to the early host response, which ultimately influences the outcome of chronic viral infection in vivo.. In vivo host responses to pathogens are complex processes involving the cooperation of many different immune cells migrating to specific tissues over time, but these events cannot be replicated in vitro. Viruses causing chronic infections are able to subvert this immune response and represent a human health burden. Here we used two well-characterized viruses that are able to persist in their natural mouse host to dissect the role of the suppressive molecule TGF-β in dampening host responses to infection in vivo. This report presents information that allows an increased understanding of long-studied TGF-β signaling by examining its direct effect on different immune cells that are activated very early after in vivo viral infection and may aid with the development of new antiviral therapeutic strategies.

Topics: Animals; Cytokines; Dendritic Cells; Female; Herpesviridae Infections; Humans; Killer Cells, Natural; Lymphocytic Choriomeningitis; Lymphocytic choriomeningitis virus; Male; Mice; Mice, Inbred C57BL; Muromegalovirus; Rodent Diseases; Signal Transduction; Transforming Growth Factor beta

The immune response to Neisseria gonorrhoeae is poorly understood, but its extensive antigenic variability and resistance to complement are thought to allow it to evade destruction by the host's immune defenses. We propose that N. gonorrhoeae also avoids inducing protective immune responses in the first place. We previously found that N. gonorrhoeae induces interleukin-17 (IL-17)-dependent innate responses in mice and suppresses Th1/Th2-dependent adaptive responses in murine cells in vitro through the induction of transforming growth factor β (TGF-β). In this study using a murine model of vaginal gonococcal infection, mice treated with anti-TGF-β antibody during primary infection showed accelerated clearance of N. gonorrhoeae, with incipient development of Th1 and Th2 responses and diminished Th17 responses in genital tract tissue. Upon secondary reinfection, mice that had been treated with anti-TGF-β during primary infection showed anamnestic recall of both Th1 and Th2 responses, with the development of antigonococcal antibodies in sera and secretions, and enhanced resistance to reinfection. In mouse knockout strains defective in Th1 or Th2 responses, accelerated clearance of primary infection due to anti-TGF-β treatment was dependent on Th1 activity but not Th2 activity, whereas resistance to secondary infection resulting from anti-TGF-β treatment during primary infection was due to both Th1- and Th2-dependent memory responses. We propose that N. gonorrhoeae proactively elicits Th17-driven innate responses that it can resist and concomitantly suppresses Th1/Th2-driven specific adaptive immunity that would protect the host. Blockade of TGF-β reverses this pattern of host immune responsiveness and facilitates the emergence of protective antigonococcal immunity.. Pathogen-host interactions during infectious disease are conventionally thought of as two-way reactions, that of the host against the pathogen and vice versa, with the outcome dependent on which one ultimately prevails. We propose that Neisseria gonorrhoeae, a pathogen that has become extremely well adapted to its exclusive human host, proactively directs the manner in which the host responds in ways that are beneficial to its own survival but detrimental to the host. Gonorrhea is a widely prevalent sexually transmitted infection, and naturally occurring gonococcal strains are becoming resistant to most available antibiotics, yet no effective vaccine has been developed. These new insights into the immune response to N. gonorrhoeae should lead to novel therapeutic strategies and facilitate new approaches to vaccine development.

Topics: Animals; Antibodies; Antibodies, Bacterial; Bodily Secretions; Disease Models, Animal; Female; Gonorrhea; Immunologic Memory; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Neisseria gonorrhoeae; Rodent Diseases; Th1 Cells; Th17 Cells; Th2 Cells; Transforming Growth Factor beta; Vagina

Innate and adaptive immunity play important protective roles by combating herpes simplex virus 1 (HSV-1) infection. Transforming growth factor β (TGF-β) is a key negative cytokine regulator of both innate and adaptive immune responses. Yet, it is unknown whether TGF-β signaling in either immune compartment impacts HSV-1 replication and latency. We undertook genetic approaches to address these issues by infecting two different dominant negative TGF-β receptor type II transgenic mouse lines. These mice have specific TGF-β signaling blockades in either T cells or innate cells. Mice were ocularly infected with HSV-1 to evaluate the effects of restricted innate or adaptive TGF-β signaling during acute and latent infections. Limiting innate cell but not T cell TGF-β signaling reduced virus replication in the eyes of infected mice. On the other hand, blocking TGF-β signaling in either innate cells or T cells resulted in decreased latency in the trigeminal ganglia of infected mice. Furthermore, inhibiting TGF-β signaling in T cells reduced cell lysis and leukocyte infiltration in corneas and trigeminal ganglia during primary HSV-1 infection of mice. These findings strongly suggest that TGF-β signaling, which generally functions to dampen immune responses, results in increased HSV-1 latency.

Topics: Animals; Disease Models, Animal; Eye; Gene Expression Regulation, Viral; Herpesvirus 1, Human; Keratitis, Herpetic; Mice; Mice, Transgenic; Rodent Diseases; Signal Transduction; Transforming Growth Factor beta; Trigeminal Ganglion; Virus Activation; Virus Latency; Virus Replication

Sirenomelia or mermaid-like phenotype is one of the principal human congenital malformations that can be traced back to the stage of gastrulation. Sirenomelia is characterized by the fusion of the two hindlimbs into a single one. In the mouse, sirens have been observed in crosses between specific strains and as the consequence of mutations that increase retinoic acid levels. We report that the loss of bone morphogenetic protein 7 (Bmp7) in combination with a half dose or complete loss of twisted gastrulation (Tsg) causes sirenomelia in the mouse. Tsg is a Bmp- and chordin-binding protein that has multiple effects on Bmp metabolism in the extracellular space; Bmp7 is one of many Bmps and is shown here to bind to Tsg. In Xenopus, co-injection of Tsg and Bmp7 morpholino oligonucleotides (MO) has a synergistic effect, greatly inhibiting formation of ventral mesoderm and ventral fin tissue. In the mouse, molecular marker studies indicate that the sirenomelia phenotype is associated with a defect in the formation of ventroposterior mesoderm. These experiments demonstrate that dorsoventral patterning of the mouse posterior mesoderm is regulated by Bmp signaling, as is the case in other vertebrates. Sirens result from a fusion of the hindlimb buds caused by a defect in the formation of ventral mesoderm.

Topics: Animals; Blotting, Western; Body Patterning; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Ectromelia; Gene Expression Regulation, Developmental; Hindlimb; Histological Techniques; In Situ Hybridization; Mesoderm; Mice; Mutation; Oligonucleotides, Antisense; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Rodent Diseases; Signal Transduction; Transforming Growth Factor beta; Xenopus; Xenopus Proteins

Connective tissue growth factor (CTGF) has been shown to mediate many actions of transforming growth factor-beta (TGF-beta) in the fibrotic response in several diseases. We compared expression of CTGF, TGF-beta, platelet-derived growth factor (PDGF), TNF-alpha, and interleukin-1 (IL-1) by in situ hybridization in Sprague-Dawley rats euthanized at 0, 2, 4, and 8 weeks after 5/6 nephrectomy using the rat remnant kidney model of renal failure. Collagen was evaluated by trichrome stains, immunohistochemistry, and electron microscopy. We compared expression patterns to cells undergoing metaplasia. Tubular epithelial regeneration and transdifferentiation to myofibroblasts were assessed morphologically and by proliferating cell nuclear antigen, smooth muscle actin, desmin, and vimentin immunohistochemistry. CTGF expression was minimal in controls, mild at 2 weeks and marked by 4 to 8 weeks in interstitial fibroblasts, coinciding with damage, regeneration, and fibrosis. TGF-beta expression was increased in many cell types at 2 weeks, increased further by 4 weeks, then remained constant. PDGF-B messenger RNA was found in many stromal cells at 2-4 weeks, but expression decreased at 8 weeks. No significant IL-1 or TNF-alpha staining was detected. We conclude that CTGF and interacting factors are associated with development or progression of chronic interstitial fibrosis. Proximity of CTGF, TGF-beta, and PDGF mRNA expression to regenerative epithelial cells and those transdifferentiating to myofibroblasts suggests that growth factors may modulate renal tubular epithelial differentiation.

Topics: Animals; Cell Differentiation; Connective Tissue Growth Factor; Desmin; Disease Models, Animal; Growth Substances; Immediate-Early Proteins; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Interleukin-1; Kidney; Kidney Diseases; Kidney Tubules; Nephrectomy; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley; Regeneration; RNA, Messenger; Rodent Diseases; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha