Mast cells control insulitis and increase Treg cells to confer protection against STZ-induced type 1 diabetes in mice.

Quantitative alterations in mast cell numbers in pancreatic lymph nodes (PLNs) have been reported to be associated with type 1 diabetes (T1D) progression, but their potential role during T1D remains unclear. In this study, we evaluated the role of mast cells in T1D induced by multiple low-dose streptozotocin (MLD-STZ) treatments, using two strains of mast cell-deficient mice (W/W(v) or Wsh/Wsh) and the adoptive transfer of mast cells. Mast cell deficient mice developed severe insulitis and accelerated hyperglycemia, with 100% of mice becoming diabetic compared to their littermates. In parallel, these diabetic mice had decreased numbers of T regulatory (Treg) cells in the PLNs. Additionally, mast cell deficiency caused a significant reduction in IL-10, TGF-ß, and IL-6 expression in the pancreatic tissue. Interestingly, IL-6-deficient mice are more susceptible to T1D associated with reduced Treg-cell numbers in the PLNs, but mast cell transfer from wild-type mice induced protection to T1D in these mice. Finally, mast cell adoptive transfer prior to MLD-STZ administration conferred resistance to T1D, promoted increased Treg cells, and decreased IL-17-producing T cells in the PLNs. Taken together, our results indicate that mast cells are implicated in resistance to STZ-induced T1D via an immunological tolerance mechanism mediated by Treg cells.

Evidence for a role of capsaicin-sensitive sensory nerves in the lung oedema induced by Tityus serrulatus venom in rats.

In the most severe cases of human envenoming by Tityus serrulatus, pulmonary oedema is a frequent finding and can be the cause of death. We have previously demonstrated a role for neuropeptides acting on tachykinin NK(1) receptors in the development of lung oedema following i.v. injection of T. serrulatus venom (TsV) in experimental animals. The present work was designed to investigate whether capsaicin-sensitive primary afferent neurons were a potential source of NK(1)-acting neuropeptides. To this end, sensory nerves were depleted of neuropeptides by neonatal treatment of rats with capsaicin. The effectiveness of this strategy at depleting sensory nerves was demonstrated by the inhibition of the neuropeptide-dependent response to intraplantar injection of formalin. Pulmonary oedema, as assessed by the levels of extravasation of Evans blue dye in the bronchoalveolar lavage and in the left lung, was markedly inhibited in capsaicin-treated animals. In contrast, capsaicin treatment failed to alter the increase in arterial blood pressure or the lethality following i.v. injection of TsV. Our results demonstrate an important role for capsaicin-sensitive sensory nerves in the cascade of events leading to lung injury following the i.v. administration of TsV.

Dexamethasone suppresses antigen-induced activation of phosphatidylinositol 3-kinase and downstream responses in mast cells.

Dexamethasone and other glucocorticoids suppress FcepsilonRI-mediated release of inflammatory mediators from mast cells. Suppression of cytokine production is attributed to repression of cytokine gene transcription but no mechanism has been described for the suppression of degranulation. We show that therapeutic concentrations of dexamethasone inhibit intermediate signaling events, in particular the activation of phosphatidylinositol (PI)3-kinase and downstream signaling events that lead to degranulation in rat basophilic leukemia 2H3 cells. This inhibitory action is mediated via the glucocorticoid receptor and is not apparent when cells are stimulated via Kit in a mouse bone marrow-derived mast cell line. The primary perturbation appears to be the failure of the regulatory p85 subunit of PI3-kinase to engage with the adaptor protein Grb2-associated binder 2 leading to suppression of phosphorylation of phospholipase Cgamma2, the calcium signal, and degranulation. Suppression of PI3-kinase activation by dexamethasone may also contribute to reduced cytokine production because the PI3-kinase inhibitor LY294002, like dexamethasone, inhibits Ag-induced transcription of cytokine genes as well as degranulation.

Tityus serrulatus scorpion venom and its toxins as tools for physiological studies

O veneno do escorpião Tityus serralatus é uma importante ferramenta para estudos fisiológicos e fisiopatológicos. O seu mecanismo básico de ação é uma estimulação das terminações nervosas do SNA, por meio da abertura de canais iônicos de membrana com liberação de catecolaminas, acetilcolina, ATP e outros mediadores responsáveis pelos efeitos observados. Esses efeitos incluem arritmias cardíacas e respiratórias, hipertensão arterial, choque, edema pulmonar, hipersecreção salivar, gástrica e pancreática, contração da musculatura lisa, liberação de citocinas e quimiocinas, lesão aguda de mucosa gástrica, pancreatite aguda e crônica e eventualmente morte. O veneno pode reproduzir essas alterações, mimetizando uma estimulação fisiológica do SNA, induzindo uma resposta imune ou ainda, possibilitando estudos da fisiopatologia do choque e seu tratamento, em modelos experimentais. Os mecanismos fisiológicos relacionados à estimulação de canais iônicos, contração da musculatura lisa por estimulação nervosa, reflexos cardiovasculares e respiratórios, secreção exócrina gastrintestinal e a cinética dos mediadores e suas interações com seus receptores específicos, podem ser estudados em interações com seus receptores específicos, podem ser estudados em humanos e animais. O estudo da fisiopatologia da intoxicação escorpiônica pode também, ser útil para a elucidação dos macanismos de edema pulmonar, arritmias cadíacas, choque circulatório, síndrome da resposta inflamatória sistêmica e falência de múltiplos órgãos, pancreatite, lesão aguda da mucosa gástrica e resposta imunológica celular e humoral. Muitos desses aspectos são discutidos nesse artigo baseado em experimentos feitos por um grupo de pesquisadores da Universidade Federal de Minas Gerais