A Crosstalk between the Smad and JNK Signaling in the TGF-β-Induced Epithelial-Mesenchymal Transition in Rat Peritoneal Mesothelial Cells

Transforming growth factor β (TGF-β) induces the process of epithelial-mesenchymal transition (EMT) through the Smad and JNK signaling. However, it is unclear how these pathways interact in the TGF-β1-induced EMT in rat peritoneal mesothelial cells (RPMCs). Here, we show that inhibition of JNK activation by introducing the dominant-negative JNK1 gene attenuates the TGF-β1-down-regulated E-cadherin expression, and TGF-β1-up-regulated α-SMA, Collagen I, and PAI-1 expression, leading to the inhibition of EMT in primarily cultured RPMCs. Furthermore, TGF-β1 induces a bimodal JNK activation with peaks at 10 minutes and 12 hours post treatment in RPMCs. In addition, the inhibition of Smad3 activation by introducing a Smad3 mutant mitigates the TGF-β1-induced second wave, but not the first wave, of JNK1 activation in RPMCs. Moreover, the inhibition of JNK1 activation prevents the TGF-β1-induced Smad3 activation and nuclear translocation, and inhibition of the TGF-β1-induced second wave of JNK activation greatly reduced TGF-β1-induced EMT in RPMCs. These data indicate a crosstalk between the JNK1 and Samd3 pathways during the TGF-β1-induced EMT and fibrotic process in RPMCs. Therefore, our findings may provide new insights into understanding the regulation of the TGF-β1-related JNK and Smad signaling in the development of fibrosis

Cell–cell and cell–matrix dynamics in intraperitoneal cancer metastasis

The peritoneal metastatic route of cancer dissemination is shared by cancers of the ovary and gastrointestinal tract. Once initiated, peritoneal metastasis typically proceeds rapidly in a feed-forward manner. Several factors contribute to this efficient progression. In peritoneal metastasis, cancer cells exfoliate into the peritoneal fluid and spread locally, transported by peritoneal fluid. Inflammatory cytokines released by tumor and immune cells compromise the protective, anti-adhesive mesothelial cell layer that lines the peritoneal cavity, exposing the underlying extracellular matrix to which cancer cells readily attach. The peritoneum is further rendered receptive to metastatic implantation and growth by myofibroblastic cell behaviors also stimulated by inflammatory cytokines. Individual cancer cells suspended in peritoneal fluid can aggregate to form multicellular spheroids. This cellular arrangement imparts resistance to anoikis, apoptosis, and chemotherapeutics. Emerging evidence indicates that compact spheroid formation is preferentially accomplished by cancer cells with high invasive capacity and contractile behaviors. This review focuses on the pathological alterations to the peritoneum and the properties of cancer cells that in combination drive peritoneal metastasis

T-CELL-DEPENDENT ANTIBODY-RESPONSE TO STAPHYLOCOCCAL-ENTEROTOXIN-B

Treatment of mice with staphylococcal enterotoxin B (SEB) induces specific T-cell tolerance to this superantigen, characterized by partial deletion of V beta 8(+) T cells in vivo and T cell anergy in vitro. In this study we examined the humoral response to SEB in BALB/c mice. Immunization of mice with SEB results in a detectable anti-SEB antibody response. Upon further treatment of mice with SEB, specific antibody levels increase significantly and the response is accelerated-characteristics of a secondary humoral response. The secondary antibody response is T cell dependent, can be transferred to T cell deficient mice with splenocytes and is composed mainly of IgM, IgGI and IgG2b isotypes, suggesting that Th2 cells provide B cell help in this response. These data demonstrate that at the same time as inducing in vitro unresponsiveness, SEB primes SEB-specific T helper cells to provide help for B cells in a secondary antibody response.42330531

THE DEVELOPMENT OF HUMORAL IMMUNOLOGICAL MEMORY TO A T-CELL-DEPENDENT ANTIGEN REQUIRES THYMIC EMIGRANT CELLS

Immunological memory is embodied in the rapid and enhanced immune responsiveness to previously encountered antigens. Classically, memory would depend on the presence of small resting long-lived specific lymphocytes which, through clonal expansion after priming with antigen, would be present at higher frequencies than in naive animals. Here we report that T-cell-reconstituted athymic mice, which lack recent thymic emigrants, mount a primary response to a T-cell-dependent antigen, but do not develop memory or the capacity to produce specific anti-TNP IgG1 antibodies during the secondary immune response. On the other hand, if thymocytes are continuously provided during the secondary response, a typical secondary immune response is achieved with high levels of specific IgG1. These results lead us to propose that the development of humoral immunological memory cannot be explained solely by the long life span of primed T lymphocytes, but is rather a dynamic state dependent on the continuous presence of recent thymic emigrants and qualitative functional differences in responder T cells.145318519

ANTI-IL-10 TREATMENT DOES NOT BLOCK EITHER THE INDUCTION OR THE MAINTENANCE OF ORALLY INDUCED TOLERANCE TO OVA

Herein, the role of IL-10 in the induction and maintenance of oral tolerance was evaluated. The results show that: (1) mice treated with MoAb anti-IL-10 are permissive to the induction of oral tolerance to OVA; (2) anti-IL-10 treatment did not reverse the in vitro blocking of T cell proliferative response found in orally-tolerized mice; and (3) orally-induced tolerance could not be broken by anti-IL-10 treatment. Taken together, these results suggest that IL-10 is not a fundamental cytokine for the establishment and maintenance of oral tolerance.41431932

A novel model of sensitization and oral tolerance to peanut protein

The prevalence of food allergic diseases is rising and poses an increasing clinical problem. Peanut allergy affects around 1% of the population and is a common food allergy associated with severe clinical manifestations. The exact route of primary sensitization is unknown although the gastrointestinal immune system is likely to play an important role. Exposure of the gastrointestinal tract to soluble antigens normally leads to a state of antigen-specific systemic hyporesponsiveness (oral tolerance). A deviation from this process is thought to be responsible for food-allergic diseases. In this study, we have developed a murine model to investigate immunoregulatory processes after ingestion of peanut protein and compared this to a model of oral tolerance to chicken egg ovalbumin (OVA). We demonstrate that oral tolerance induction is highly dose dependent and differs for the allergenic proteins peanut and OVA. Tolerance to peanut requires a significantly higher oral dose than tolerance to OVA. Low doses of peanut are more likely to induce oral sensitization and increased production of interleukin-4 and specific immunoglobulin E upon challenge. When tolerance is induced both T helper 1 and 2 responses are suppressed. These results show that oral tolerance to peanut can be induced experimentally but that peanut proteins have a potent sensitizing effect. This model can now be used to define regulatory mechanisms following oral exposure to allergenic proteins on local, mucosal and systemic immunity and to investigate the immunomodulating effects of non-oral routes of allergen exposure on the development of allergic sensitization to peanut and other food allergens