RESUMO
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a high mortality rate. The clinical course is attributed to the severity of pneumonia and systemic complications. In COVID-19 patients and murine models of SARS-CoV-2 infection, the disease may be accompanied by excessive production of cytokines, leading to an accumulation of immune cells in affected organs such as lungs. Previous reports have shown that SARS-CoV-2 infection antagonizes interferon (IFN)-dependent antiviral response, thereby preventing the expression of IFN-stimulated genes (ISGs). Lower IFN levels have been linked to more-severe COVID-19. Interleukin 27 (IL27) is a heterodimeric cytokine composed of IL27p28 and EBI3 subunits, which induce both pro- and anti-inflammatory responses. Recently, we and others have reported that IL27 also induces a strong antiviral response in an IFN-independent manner. Here, we investigated transcription levels of both IL27 subunits in COVID-19 patients. The results show that SARS-CoV-2 infection modulates TLR1/2-MyD88 signaling in PBMCs and monocytes and induces NF-κB activation and expression of NF-κB-target genes that are dependent on a robust pro-inflammatory response, including EBI3; and activates IRF1 signaling which induces IL27p28 mRNA expression. The results suggest that IL27 induces a robust STAT1-dependent pro-inflammatory and antiviral response in an IFN-independent manner in COVID-derived PBMCs and monocytes as a function of a severe clinical course of COVID-19. Similar results were observed in macrophages stimulated with the SARS-CoV-2 spike protein. Thus, IL27 can trigger an antiviral response in the host, suggesting the possibility of novel therapeutics against SARS-CoV-2 infection in humans.
Assuntos
COVID-19 , Interleucina-27 , Humanos , Antivirais/uso terapêutico , COVID-19/imunologia , Citocinas , Progressão da Doença , Interleucina-27/imunologia , NF-kappa B , SARS-CoV-2RESUMO
In chronic Chagas disease, Trypanosoma cruzi-specific T-cell function decreases over time, and alterations in the homeostatic IL-7/IL-7R axis are evident, consistent with a process of immune exhaustion. IL-27 is an important immunoregulatory cytokine that shares T-cell signaling with IL-7 and other cytokines of the IL-12 family and might be involved in the transcriptional regulation of T-cell function. Here, we evaluated the expression and function of IL-27R in antigen-experienced T cells from subjects with chronic Chagas disease and assessed whether in vitro treatment with IL-27 and IL-7 might improve T. cruzi-specific polyfunctional T-cell responses. In vitro exposure of PBMCs to T. cruzi induced a downregulation of IL-27R in CD4+ T cells and an upregulation in CD8+ T cells in subjects without heart disease, while IL-27R expression remained unaltered in subjects with more severe clinical stages. The modulation of IL-27R was associated with functional signaling through STAT3 and STAT5 and induction of the downstream genes TBX21, EOMES and CXCL9 in response to IL-27. In vitro treatment of PBMCs with IL-27 and IL-7 improved monofunctional and polyfunctional Th1 responses, accompanied by the induction of IL-10 and Bcl-2 expression in subjects without heart disease but did not improve those in subjects with cardiomyopathy. Our findings support the process of desensitization of the IL-27/IL-27R pathway along with disease severity and that the pro-inflammatory and immunomodulatory mechanisms of IL-27 might be interconnected.
Assuntos
Doença de Chagas/imunologia , Interleucina-27/imunologia , Adulto , Idoso , Linfócitos T CD8-Positivos/imunologia , Doença de Chagas/genética , Doença de Chagas/parasitologia , Doença Crônica , Feminino , Humanos , Interleucina-27/genética , Interleucina-7/genética , Interleucina-7/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina/genética , Receptores de Interleucina/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Trypanosoma cruzi/genética , Trypanosoma cruzi/fisiologiaRESUMO
BACKGROUND: IL-27 has dual roles in the immune response either stimulating Th1 or inhibiting Th17 cells. Because there is a particular link of IL-23/Th17 axis in the development of cancer and IL-27 has been considered a potential treatment for cancer, we evaluated the gastric and serum concentrations of IL-27 in two mutually exclusive Helicobacter pylori-associated diseases, gastric cancer (GC) and duodenal ulcer (DU). MATERIAL AND METHODS: We prospectively studied 110 H pylori-positive patients and 40 healthy blood donors. Serum and gastric concentrations of IL-27 and cytokines of the Th1/Th17 cells were assessed by ELISA. RESULTS: IL-27 was not detected in GC patients, but the cytokine concentration was very high in the patients with DU. IL-27 was also detected in the gastritis patients and in the H pylori-positive blood donors. IL27RA mRNA expression in peripheral blood mononuclear cells, evaluated by rt-PCR, was stimulated by H pylori strains. The cytokine concentration positively correlated with the Th1 and negatively with Th17 cell representative cytokine levels. Gastric IL-27 concentrations were positively correlated with increased degree of mononuclear and polymorphonuclear cells on the antral gastric mucosa of DU patients in consonance with the DU gastritis pattern. IL-12p70 and IFN-γ gastric concentrations were significantly higher in DU than in GC. Conversely, gastric concentrations of Th17 cell-associated cytokines (IL-1ß, IL-6, IL-17A, IL-23, and TGF-ß) were significantly higher in GC than in DU patients. CONCLUSION: Although H pylori infection is able to elicit IL-27 and IL-27Rα secretion, DU and GC have diametrically opposed cytokine patterns.