RESUMO
Paracoccidioidomycosis (PCM) is a systemic fungal disease caused by Paracoccidioides spp., whose clinical outcome depends on immune response. Interleukin 32 (IL-32) is a cytokine present in inflammatory and infectious diseases, including bacterial, virus and protozoan infections. Its role in fungal disease remains unclear. The axis IL-15, IL-32 and vitamin D leads to microbicidal capacity against intracellular pathogens. Thus, the aims of this study were to investigate the production of IL-32 during Paracoccidioides spp. infection and whether this cytokine and IL-15 can increase P. brasiliensis control in a vitamin D dependent manner. IL-32 was highly detected in oral lesions from patients with PCM. In addition, high production of this cytokine was intracellularly detected in peripheral blood mononuclear cells (PBMCs) from healthy donors after exposure to particulated P. brasiliensis antigens (PbAg). The IL-32γ isoform was predominantly expressed, but there was mRNA alternative splicing for IL-32α isoform. The induction of IL-32 was dependent on Dectin-1 receptor. Infection of PBMCs with P. brasiliensis yeasts did not significantly induce IL-32 production even after activation with exogenous IFN-γ or IL-15 treatments. Although IL-15 was a potent inducer of IL-32 production, treatment with this cytokine did not increase the fungal control unless vitamin D was present in high levels. In this case, both IL-15 and IL-32 increased fungicidal activity of PBMCs. Together, data showed that IL-32 is present in lesions of PCM, PbAg induces IL-32, and the axis of IL-15/IL-32/vitamin D can contribute to control fungal infection. The data suggest that exposure to molecules from P. brasiliensis, as ß-glucans, is needed to induce IL-32 production since only heat-killed and sonicated P. brasiliensis yeasts were able to increase IL-32, which was blocked by anti-Dectin-1 antibodies. This is the first description about IL-15/IL-32/vitamin D pathway role in P. brasiliensis infection.
Assuntos
Paracoccidioides , Paracoccidioidomicose , Humanos , Interleucina-15 , Interleucinas , Leucócitos Mononucleares , Vitamina DRESUMO
OBJECTIVE: Multiple sclerosis (MS) is a multifactorial chronic disease that affects the central nervous system (CNS). Toll-like receptors (TLRs) play a central role in cytokine production after pathogen- and danger-associated molecular patterns (PAMPs and DAMPs) and contribute to CNS damage in MS patients. Here, we evaluated the effects of interferon (IFN)-ß treatment in TLR2 and TLR4-dependent cytokine production and mRNA expression in whole-blood cell cultures from MS patients. METHODS: We evaluated cytokine production by ELISA from whole-blood cell culture supernatants and mRNA expression by real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMCs). RESULTS: In patients treated with IFN-ß, tumor necrosis factor (TNF)-α production after exposure to TLR2 agonist (Pam3Cys) was lower than in healthy controls and untreated MS patients. However, IFN-ß treatment had no significant effect on TNF-α production after TLR4 agonist (LPS) stimulation. On the other hand, interleukin (IL)-10 production was increased in TLR4- but not in TLR2-stimulated whole-blood cell culture from MS patients under IFN-ß treatment when compared to the controls. No differences in TNF-α or IL-10 mRNA expression in PBMCs from healthy controls and untreated or treated MS patients were detected, although PBMCs from treated patients presented higher levels of IL-32γ mRNA than those from controls. CONCLUSIONS: Our data suggest that IFN-ß treatment alters the TLR-dependent immune response of PBMCs from MS patients. This may contribute to the beneficial effects of IFN-ß treatment.
Assuntos
Interferon beta/uso terapêutico , Interleucina-10/biossíntese , Esclerose Múltipla/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Adulto , Citocinas/biossíntese , Citocinas/efeitos dos fármacos , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologiaRESUMO
Interleukin 32 (IL-32) is an intracellular cytokine produced by immune and non immune cells after different stimuli. It contributes to inflammation and control of intracellular pathogens mainly by inducing proinflammatory cytokines and microbicidal molecules. Evidence is rising showing that IL-32 can be considered an endogenous danger signal after tissue injury, amplifying the inflammatory process and acquired immune responses. It seems to be a master regulator of intracellular infectious diseases. In this review, first the general properties of IL-32 are described followed by its role in the immunopathogenesis of inflammatory and infectious diseases. Roles of IL-32 in the control of infectious diseases caused by intracellular pathogens are reported, and later a focus on IL-32 in leishmaniases, diseases caused by an intracellular protozoan, is presented.
Assuntos
Mediadores da Inflamação/imunologia , Interleucinas/imunologia , Espaço Intracelular/imunologia , Leishmania/imunologia , Leishmaniose/imunologia , Transdução de Sinais/imunologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Interações Hospedeiro-Parasita/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Interleucinas/metabolismo , Espaço Intracelular/parasitologia , Leishmania/fisiologia , Leishmaniose/metabolismo , Leishmaniose/parasitologiaRESUMO
Visceral leishmaniasis (VL) is a chronic parasitic disease caused by Leishmania infantum in the Americas. During VL, several proinflammatory cytokines are produced in spleen, liver, and bone marrow. However, the role of interleukin-32 (IL-32) has not been explored in this disease. IL-32 can induce production of proinflammatory cytokines in innate immune cells and polarize the adaptive immune response. Herein, we discovered that L. infantum antigens induced expression of mRNA mainly for the IL-32γ isoform but also induced low levels of the IL-32ß transcript in human peripheral blood mononuclear cells. Furthermore, infection of human IL-32γ transgenic mice (IL-32γTg mice) with L. infantum promastigote forms increased IL-32γ expression in the spleen and liver. Interestingly, IL-32γTg mice harbored less parasitism in the spleen and liver than wild-type (WT) mice. In addition, IL-32γTg mice showed increased granuloma formation in the liver compared to WT mice. The protection against VL was associated with increased production of nitric oxide (NO), interferon gamma (IFN-γ), IL-17A, and tumor necrosis factor alpha by splenic cells restimulated ex vivo with L. infantum antigens. In parallel, there was an increase in the number of Th1 and Th17 T cells in the spleens of IL-32γTg mice infected with L. infantum IL-32γ induction of IFN-γ and IL-17A expression was found to be essential for NO production by splenic cells of infected animals. These data indicate that IL-32γ potentiates the Th1/Th17 immune response during experimental VL, thus contributing to the control of L. infantum infection.