Most congenital transmissions of Trypanosoma cruzi are not detected. As the levels of mediators regulating the immune response might be different in the absence or in the presence of transmission, we explored the levels of tumor necrosis factor (TNF) and soluble TNF receptors TNF-R1 and -R2 in T. cruzi-infected pregnant women and the neonates. We previously found that the circulating levels of TNF were higher in non-transmitting than in transmitting pregnant women. This observation has now been extended to the spontaneous release of TNF by peripheral blood leukocytes (PBLs) that was also higher in non-transmitting than in transmitting pregnant women. As their mothers, non-infected neonates had higher circulating levels of TNF than congenitally infected children. The circulating levels of sTNF-R1 increased in non-transmitting and transmitting mothers and in infected and non-infected neonates. The circulating levels of sTNF-R2 were approximately 60% higher in infected than in non-infected neonates (1,635 +/- 101 and 1,027 +/- 100 pg/mL, respectively) and remained higher at 1 year of age. This important increase, only observed in infected neonates, could be useful to orientate to the presence of vertical transmission of T. cruzi infection.
Summary Serine leucocyte proteinase inhibitor (SLPI) is the main serine proteinase inhibitor produced by epithelial cells and has been shown to be a pleiotropic molecule with anti‐inflammatory and microbicidal activities. However, the role of SLPI on the adaptive immune response is not well established. Therefore, we evaluated the effect of SLPI on lymphocyte proliferation and cytokine production. Human peripheral blood mononuclear cells (PBMC) were treated with mitogens plus SLPI and proliferation was assessed by [3H]thymidine uptake. The SLPI decreased the lymphocyte proliferation induced by interleukin‐2 (IL‐2) or OKT3 monoclonal antibodies in a dose‐dependent manner. Inhibition was not observed when depleting monocytes from the PBMC and it was restored by adding monocytes and SLPI. SLPI‐treated monocyte slightly decreased MHC II and increased CD18 expression, and secreted greater amounts of IL‐4, IL‐6 and IL‐10 in the cell culture supernatants. SLPI‐treated monocyte culture supernatant inhibited the CD4+ lymphocyte proliferation but did not affect the proliferation of CD8+ cells. Moreover, IL‐2 increased T‐bet expression and the presence of SLPI significantly decreased it. Finally, SLPI‐treated monocyte culture supernatant dramatically decreased interferon‐γ but increased IL‐4, IL‐6 and IL‐10 in the presence of IL‐2‐treated T cells. Our results demonstrate that SLPI target monocytes, which in turn inhibit CD4 lymphocyte proliferation and T helper type 1 cytokine secretion. Overall, these results suggest that SLPI is an alarm protein that modulates not only the innate immune response but also the adaptive immune response.
Secretory Leukocyte Proteinase Inhibitor (SLPI) is an antiinflammatory peptide that blocks the activity of serine proteases, primarily the neutrophil elastase. In an attempt to direct the activity of SLPI on inflamed sites, a chimera consisting of the transglutaminase II substrate domain of trappin 2 (cementoin), and the mature SLPI protein was constructed. Cell attachment and biological activity were compared between SLPI and this chimera. By using whole cell ELISA, fluorescence microscopy and flow cytometry assays we observed that the cementoin-SLPI fusion protein (FP) but not SLPI attached to a human lung epithelial cell line and monocytes. A maximum attachment was achieved 15 min after FP was added to the cell cultures. In an elastase activity assay, we observed that FP retained its antiprotease activity and that at equimolar amount of proteins, FP was more efficient than SLPI in the inhibition. Both, FP and SLPI inhibits IL-2-induced lymphocyte proliferation, however, lower amounts of FP were required to achieve this inhibition. Furthermore, FP binds to mycobacteria and maintained the bactericidal activity observed for SLPI. Overall, these results show that this new chimera is able to attach to the cell surfaces retaining and improving some biological activities described for SLPI.
A new green synthesis and anti-tumor activity of the series of bis (3-arylimidazolidinyl-1) methanes 1 -6 are described. The compounds were synthesized from the corresponding N-arylethylenediamine and trioxane as sources of formaldehyde and the reactions were performed in heterogeneous phase catalyzed by an acidic ion-exchange resin (Amberlyst 15). The compounds were tested with the Sulforhodamine B assay according to the protocol of the National Cancer Institute for several cell lines. The results were expressed as percentage inhibition of growth cell in comparison with the full growth of the cells without treatment. Cytotoxicity on normal cells using the Annexing-PI staining and flow cytometry has been evaluated. The parent compound, bis(3-phenylimidazolidinyl-1)methane 1 and the monohalogenated derivatives 4-chlorophenyl 3 and 3-bromophenyl 5 showed antineoplastic activity, 60%, 82% and 89% inhibition growth cell respectively on the human colon cell line (HCT116). The 4-tolyl derivative 6 presented inhibitory activity (73% inhibition of growth cell) on human lung adenocarcinoma cell line (A549) and 62% on human mammary cell line MCF-7.
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