Navegando por Palavras-chave "macrophage migration inhibitory factor"

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    Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma
    (Frontiers Media Sa, 2018) Figueiredo, Carlos Rogerio [UNIFESP]; Azevedo, Ricardo Alexandre de [UNIFESP]; Mousdell, Sasha; Resende-Lara, Pedro T.; Ireland, Lucy; Santos, Almudena; Girola, Natalia [UNIFESP]; Cunha, Rodrigo L. O. R.; Schmid, Michael C.; Polonelli, Luciano; Travassos, Luiz Rodolpho [UNIFESP]; Mielgo, Ainhoa
    Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. While immunotherapies have shown a remarkable success in melanoma treatment, patients develop resistance by mechanisms that include the establishment of an immune suppressive tumor microenvironment. Thus, understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that macrophages (MOs) and dendritic cells (DCs) are suppressed in metastatic melanoma and that the Ig-CDR-based peptide C36L1 is able to restore MOs and DCs' antitumorigenic and immunogenic functions and to inhibit metastatic growth in lungs. Specifically, C36L1 treatment is able to repolarize M2-like immunosuppressive MOs into M1-like antitumorigenic MOs, and increase the number of immunogenic DCs, and activated cytotoxic T cells, while reducing the number of regulatory T cells and monocytic myeloid-derived suppressor cells in metastatic lungs. Mechanistically, we find that C36L1 directly binds to the MIF receptor CD74 which is expressed on MOs and DCs, disturbing CD74 structural dynamics and inhibiting MIF signaling on these cells. Interfering with MIF-CD74 signaling on MOs and DCs leads to a decrease in the expression of immunosuppressive factors from MOs and an increase in the capacity of DCs to activate cytotoxic T cells. Our findings suggest that interfering with MIF-CD74 immunosuppressive signaling in MOs and DCs, using peptide-based immunotherapy can restore the antitumor immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the antitumor immune response in metastatic melanoma.
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    Macrophage Migration Inhibitory Factor in the Paraventricular Nucleus Plays a Major Role in the Sympathoexcitatory Response to Salt
    (Lippincott Williams & Wilkins, 2010-11-01) Colombari, Eduardo [UNIFESP]; Colombari, Debora Simões de Almeida; Li, Hongwei; Shi, Peng; Dong, Ying; Jiang, Nan; Raizada, Mohan K.; Sumners, Colin; Murphy, David; Paton, Julian Francis Richmond; Univ Bristol; Univ Florida; São Paulo State Univ; Universidade Federal de São Paulo (UNIFESP)
    Central hyperosmotic stimulation (HS) evokes increases in sympathetic nerve activity mediated by activation of angiotensin type 1 receptors in the hypothalamic paraventricular nucleus (PVN). Macrophage inhibitory migration factor (MIF) is an intracellular inhibitory regulator of angiotensin type 1 receptor-mediated actions of angiotensin II within neurons of the PVN. MIF mediates its actions via its intrinsic thiol-protein oxidoreductase activity. We demonstrate that intracerebroventricular injection of hypertonic saline into Sprague-Dawley rats elicits a significant (approximate to 112%) increase in MIF mRNA expression in the PVN. Next, we evaluated the effect of viral-mediated expression of either MIF or [C60S]-MIF (which lacks thiol-protein oxidoreductase activity) in the PVN on the sympathoexcitation evoked by HS. We used a decorticate, arterially perfused in situ preparation of male Wistar rats (60 to 80 g). HS was induced by raising perfusate osmolality from 290 to 380 milliosmoles for 40 seconds. Seven to 10 days before experiments, rats were injected bilaterally (500 nL per side) with 0.9% saline (control) or with adenoassociated virus to express MIF, [C60S]-MIF, or enhanced green fluorescent protein in the PVN. HS produced sympathoexcitation in both the 0.9% saline and enhanced green fluorescent protein groups (sympathetic nerve activity increase of +27 +/- 4% and +25 +/- 4%, respectively; P<0.05), an effect that was not observed in the MIF group (+4 +/- 5%). Conversely, the HS-induced increase in sympathetic nerve activity was potentiated in the [C60S]-MIF group (+45 +/- 6%; P<0.05). We propose that MIF acting within the PVN is a major counterregulator of HS-induced sympathoexcitation, an effect that depends on thiol-protein oxidoreductase activity. (Hypertension. 2010;56:956-963.)