ABSTRACT
BACKGROUND: Chemokine levels in severe coronavirus disease 2019 (COVID-19) patients have been shown to be markedly elevated. But the role of chemokines in mild COVID-19 has not yet been established. According to the epidemiological statistics, most of the COVID-19 cases in Shiyan City, China, have been mild. The purpose of this study was to evaluate the level of chemokines in mild COVID-19 patients and explore the correlation between chemokines and host immune response. METHODS: In this study, we used an enzyme-linked immunosorbent assay to detect serum levels of chemokines in COVID-19 patients in Shiyan City. Expression of chemokine receptors and of other signaling molecules was measured by real-time polymerase chain reaction. RESULTS: We first demonstrated that COVID-19 patients, both sever and mild cases, are characterized by higher level of chemokines. Specifically, monocyte chemotactic protein 1 (MCP-1) is expressed at higher levels both in severe and mild cases of COVID-19. The receptor of MCP-1, C-C chemokine receptor type 2, was expressed at higher levels in mild COVID-19 patients. Finally, we observed a significant negative correlation between expression levels of interferon (IFN) regulatory factor 3 (IRF3) and serum levels of MCP-1 in mild COVID-19 patients. CONCLUSION: Higher expression of MCP-1 in mild COVID-19 patients might be correlated with inhibition of IFN signaling. The finding adds to our understanding of the immunopathological mechanisms of severe acute respiratory syndrome coronavirus 2 infection and provides potential therapeutic targets and strategies.
Subject(s)
COVID-19/immunology , Chemokine CCL2/blood , Chemokines/blood , Interferon Type I/metabolism , Adult , COVID-19/metabolism , COVID-19/physiopathology , China , Disease Progression , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interferon Regulatory Factor-3/blood , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Receptors, CCR2/blood , Signal Transduction/immunologyABSTRACT
The present study aimed to investigate alterations in Tolllike receptor 4 (TLR4), interferon regulatory factor 5 (IRF5) and interferonγinducible protein10 (IP10), and evaluate whether these factors may be associated with a sustained virological response (SVR) among patients with hepatitis C virus genotype1 (HCV1) who were treated with peginterferon plus ribavirin (PEGIFNRBV). A total of 31 Chinese patients infected with HCV1 were enrolled in the present study and 25 patients obtained SVR. The expression levels of IP10 declined significantly during PEGIFNRBV therapy at the 24 and 48 week timepoints, compared with the baseline (P<0.005, 0.001 and 0.001, respectively). In addition, it was observed that IRF5 mRNA expression and the number of TLR4+ peripheral blood mononuclear cells exhibited similar correlations with IP10 concentration (R2=0.0726, P=0.001, R2=0.1634, P<0.0001, respectively) in the SVR group patients; however, these correlations were not observed to be present in the nonSVR group patients. In conclusion, the results of the present study suggest that marked alterations in IP10, TLR4 and IRF5 expression may serve as indicators for the development of SVR in patients with HCV1 treated with PEGIFNRBV.
Subject(s)
Antiviral Agents/therapeutic use , Hepacivirus/drug effects , Hepatitis C/blood , Hepatitis C/drug therapy , Interferon-alpha/therapeutic use , Polyethylene Glycols/therapeutic use , Ribavirin/therapeutic use , Adult , Chemokine CXCL10/blood , Female , Humans , Interferon Regulatory Factor-3/blood , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factors/blood , Interferon Regulatory Factors/genetics , Leukocytes, Mononuclear/cytology , Male , Middle Aged , RNA, Messenger/genetics , Recombinant Proteins/therapeutic use , Toll-Like Receptor 4/analysis , Toll-Like Receptor 4/blood , Viral Load/drug effectsABSTRACT
OBJECTIVE: The aim was to investigate the level of interferon regulatory factor (IRF) 1, 3, and 7 in peripheral blood cells from patients with primary Sjogren syndrome (pSS) and to determine whether and where IRF1 exists in the parotid glands of pSS. METHODS: Peripheral blood cells and parotid gland biopsy specimens from patients with pSS were studied. The IRF1, IRF3, and IRF7 gene mRNA levels in peripheral blood cells were calculated by using real-time PCR. The IRF1-positive cells in the parotid glands with pSS were observed by using immunohistochemistry and immunofluorescence. Statistical analysis was performed by Student t test. RESULTS: Compared with 24 control samples, the IRF1 mRNA levels in peripheral blood cells of 37 cases with pSS were up-regulated (P < .05), but the IRF3 and IRF7 mRNA levels of pSS were not up-regulated (P > .05). Relative quantitative levels of IRF1 mRNA were 2.17-fold higher in pSS patients than control subjects. The IRF1-positive cells of the pSS group were localized in the epithelial islands, lymphocytes, and ductal epithelial cells of the parotid glands. In all control subjects, the IRF1-positive cells were localized only to the ductal epithelial cells of parotid glands as determined by immunohistochemical staining or immunofluorescence. The scores of IRF1-positive cells of pSS were significantly higher than that of control samples (P < .05). CONCLUSION: These findings indicate that IRF1 mRNA levels are up-regulated in the peripheral blood cells of pSS patients. Also, IRF1-positive cells exist in the epithelial islands, lymphocytes, and ductal epithelial cells of the parotid glands of individuals affected by pSS, but are limited to the ductal epithelial cells of healthy control subjects.
Subject(s)
Interferon Regulatory Factors/biosynthesis , Sjogren's Syndrome/immunology , Sjogren's Syndrome/metabolism , Adult , Aged , Case-Control Studies , Epithelial Cells/metabolism , Female , Fluorescent Antibody Technique , Gene Expression , Humans , Interferon Regulatory Factor-1/biosynthesis , Interferon Regulatory Factor-1/genetics , Interferon Regulatory Factor-3/biosynthesis , Interferon Regulatory Factor-3/blood , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-7/biosynthesis , Interferon Regulatory Factor-7/blood , Interferon Regulatory Factor-7/genetics , Interferon Regulatory Factors/blood , Interferon Regulatory Factors/genetics , Lymphocytes/metabolism , Male , Middle Aged , Parotid Gland/metabolism , RNA, Messenger/blood , Reverse Transcriptase Polymerase Chain Reaction , Sjogren's Syndrome/blood , Sjogren's Syndrome/genetics , Up-Regulation , Young AdultABSTRACT
The synthesis of interferon-beta (IFNbeta) and IFN-inducible factors elicited by lipopolysaccharide (LPS) depends on the transcriptional activity of interferon regulatory factor 3 (IRF-3) downstream of Toll-like receptor-4 (TLR4). To examine the ability of human newborns to mount TLR4-mediated IRF-3-dependent responses, we analyzed the pattern of genes expressed on the addition of LPS to cord blood or cord blood monocyte-derived dendritic cells (moDCs). Expression of IFNbeta and IFN-inducible genes was selectively impaired in neonatal blood and moDCs as compared with their adult counterparts. This selective defect was confirmed by microarray experiments on moDCs. Altered expression of IFN-inducible genes was related to impaired IFNbeta synthesis because IFNbeta signaling was functional in neonatal moDCs. However, addition of exogenous IFNbeta failed to restore LPS-induced IL-12p70 synthesis which was previously shown to be defective in neonatal moDCs. Although LPS-induced IRF-3 nuclear translocation was observed both in adult and neonatal moDCs, IRF-3 DNA-binding activity and association with the coactivator CREB-binding protein (CBP) were decreased in neonatal as compared with adult moDCs. We conclude that impaired IRF-3/CBP interaction in neonatal blood cells exposed to LPS is associated with impaired expression of IFNbeta and IFN-inducible genes. Because IRF-3 activity is also required for IL-12p70 synthesis, our findings provide a molecular basis for the decreased ability of LPS-stimulated neonatal moDCs to elicit Th1-type responses.