C-Reactive Protein Controls IL-23 Production by Human Monocytes

Geyer, Chiara E.; Newling, Melissa; Sritharan, Lathees; Griffith, Guillermo R.; Chen, Hung Jen; Baeten, Dominique; Dunnen, Jeroen den

doi:10.3390/ijms222111638

Cited by 8 publications

(7 citation statements)

References 64 publications

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“…Serum IL-23 levels were significantly elevated in patients with SLE compared to healthy individuals and correlated with overall SLE disease activity as measured by SLEDAI [60]. Furthermore, the increased c-reactive protein levels observed in inflammatory conditions, especially during flares of the disease can be linked specifically with the IL-23 production in monocytes [58]. Despite the recently published phase 3 trial [33,34], our findings indicate that the IL-12/IL-23 inhibitor "ustekinumab" may efficiently disrupt the molecular interaction network of monocytes and therefore some patients might indeed benefit from this drug.…”

Section: Discussionmentioning

confidence: 91%

Restoration of aberrant gene expression of monocytes in systemic lupus erythematosus via a combined transcriptome-reversal and network-based drug repurposing strategy

et al. 2023

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Background Monocytes -key regulators of the innate immune response- are actively involved in the pathogenesis of systemic lupus erythematosus (SLE). We sought to identify novel compounds that might serve as monocyte-directed targeted therapies in SLE. Results We performed mRNA sequencing in monocytes from 15 patients with active SLE and 10 healthy individuals. Disease activity was assessed with the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K). Leveraging the drug repurposing platforms iLINCS, CLUE and L1000CDS2, we identified perturbagens capable of reversing the SLE monocyte signature. We identified transcription factors and microRNAs (miRNAs) that regulate the transcriptome of SLE monocytes, using the TRRUST and miRWalk databases, respectively. A gene regulatory network, integrating implicated transcription factors and miRNAs was constructed, and drugs targeting central components of the network were retrieved from the DGIDb database. Inhibitors of the NF-κB pathway, compounds targeting the heat shock protein 90 (HSP90), as well as a small molecule disrupting the Pim-1/NFATc1/NLRP3 signaling axis were predicted to efficiently counteract the aberrant monocyte gene signature in SLE. An additional analysis was conducted, to enhance the specificity of our drug repurposing approach on monocytes, using the iLINCS, CLUE and L1000CDS2 platforms on publicly available datasets from circulating B-lymphocytes, CD4+ and CD8+ T-cells, derived from SLE patients. Through this approach we identified, small molecule compounds, that could potentially affect more selectively the transcriptome of SLE monocytes, such as, certain NF-κB pathway inhibitors, Pim-1 and SYK kinase inhibitors. Furthermore, according to our network-based drug repurposing approach, an IL-12/23 inhibitor and an EGFR inhibitor may represent potential drug candidates in SLE. Conclusions Application of two independent - a transcriptome-reversal and a network-based -drug repurposing strategies uncovered novel agents that might remedy transcriptional disturbances of monocytes in SLE.

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Section: Discussionmentioning

confidence: 91%

Restoration of aberrant gene expression of monocytes in systemic lupus erythematosus via a combined transcriptome-reversal and network-based drug repurposing strategy

et al. 2023

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“…Patel et al (68) showed that IL-17 stimulates CRP expression in hepatocytes and coronary artery smooth muscle cells and mediates CRP induction via p38 MAPK and ERK1/2-dependent NF-ĸB and C/EBPβ activation independently of IL-1β and IL-6. Moreover, a recent study showed that CRP increased IL-23 production by promoting gene transcription of IL23A (69). However, these studies cannot explain the increased expression of these cytokines under conditions of extremely low hs-CRP concentrations.…”

Section: Discussionmentioning

confidence: 94%

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY)

DIREN¹,

Demirci

Gül

et al. 2022

In Vivo

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Background/Aim: High-sensitivity C-reactive protein (hs-CRP) is used in the differential diagnosis of maturity-onset diabetes of the young (MODY)-3, but other inflammatory markers have not been investigated in MODY patients. We aimed to compare the serum levels of antiinflammatory and proinflammatory cytokines between MODY patients and healthy subjects and show the inflammatory features in MODY subtypes. Patients and Methods: Thirty patients with clinically suspected MODY and 34 healthy controls were included in this study. Nextgeneration sequencing (NGS) was used for the molecular diagnosis of MODY subtypes. Serum levels of cytokines were measured using a multiplexed cytokine assay and hs-CRP concentration was determined by the immunoturbidimetric assay. Results: The hs-CRP levels were higher in both NGSconfirmed (MODY, n=17) (p=0.009) and n=13) patients (p<0.001) than those in controls. However, , , , , and sCD40L (p=0.007) levels of MODY patients and IL-1β (p=0.002), IL-31 (p<0.001), , and sCD40L (p=0.039) levels of non-MODY patients were lower than those of controls. While hs-CRP levels were lower in MODY3 patients than non-MODY3 patients (p=0.009), IL-17A (p=0.006) and IL-23 (p=0.016) levels for the first time in this study were found to be higher in patients with MODY3 than in patients with other MODY subtypes (p<0. 05). Conclusion: MODY patients had lower serum levels of the proinflammatory cytokines IL-1β, IL-6, TNF-α, IL-31, and sCD40L compared to healthy controls. High IL-17A and IL-23 levels along with low hs-CRP levels may be potential markers to distinguish MODY3 from other MODY subtypes.Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes and comprises about 1-5% of total diabetes (1). The prevalence of MODY has been increasing like other forms of diabetes in Turkey (2). The diagnostic criteria specified in the Practice Guideline for MODY in 2018 are evidence of endogenous insulin secretion, diabetes-onset before the age of 25 in at least one family member, presence of diabetes in two consecutive generations, and absence of autoantibodies to pancreatic islet antigens (1, 3). Mutations in genes responsible for beta cells' development and function cause MODY. To date, different mutations in fourteen genes (HNF4A/MODY1, GCK/MODY2, HNF1A/MODY3, PDX1/MODY4, HNF1B/MODY5, NEUROD1/MODY6, KLF11/ MODY7, CEL/MODY8, PAX4/MODY9, INS/MODY10, BLK/ MODY11, ABCC8/MODY12, KCNJ11/MODY13, and APPL1/ MODY14) have been described as responsible for the pathogenesis of MODY subtypes (3, 4). Recent studies have suggested that some possible biomarkers such as urine and serum amino acids, complement 5 and 8, transthyretin, urine glucose, apolipoprotein M (ApoM), lipid profile, D-glycan index, and cystatin C are useful for the differential diagnosis of 2490

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“…In addition to elevated IL-10 levels, TNF-α and IL-23 were also increased in serum of COVID-19 patients and correlated positively with CRP levels. It has been previously investigated that CRP can induce TNF-α and IL-23 production by monocytes ( 33 , 34 ), so the elevation of TNF-α and IL-23 in COVID-19 patients might be related to CRP-induced monocytes. IL-23, in turn, can promote Th17 proliferation and differentiation, which releases the pro-inflammatory cytokine IL-17 and enhances inflammation ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Serum IL-23, IL-10, and TNF-α predict in-hospital mortality in COVID-19 patients

et al. 2023

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ObjectiveThe hyperinflammatory response, caused by severe acute respiratory syndrome-2 (SARS-CoV-2), is the most common cause of death in patients with coronavirus disease 2019 (COVID-19). The etiopathogenesis of this illness is not fully understood. Macrophages appear to play a key part in COVID-19’s pathogenic effects. Therefore, this study aims to examine serum inflammatory cytokines associated with the activation state of macrophages in COVID-19 patients and attempt to find accurate predictive markers for disease severity and mortality risk in hospital.Methods180 patients with COVID-19 and 90 healthy controls (HCs) participated in this study. Patients were divided into three different subgroups, mild (n=81), severe (n=60), and critical groups (n=39). Serum samples were collected and IL (Interleukin)-10, IL-23, tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), IL-17, monocyte chemoattractant protein-1 (MCP-1) and chemokine ligand 3 (CCL3) were determined by ELISA. In parallel, myeloperoxidase (MPO) and C-reactive protein (CRP) were measured using colorimetric and electrochemiluminescence methods, respectively. Data were collected, and their associations with disease progression and mortality were assessed using regression models and receiver operating characteristic (ROC) curves.ResultsCompared to HCs, a significant increase in IL-23, IL-10, TNF-α, IFN-γ and MCP-1, were observed in COVID-19 patients. Serum levels of IL-23, IL-10, and TNF-α were significantly higher in COVID-19 patients with critical cases compared to mild and severe cases, and correlated positively with CRP level. However, non-significant changes were found in serum MPO and CCL3 among the studied groups. Moreover, significant positive association has been observed among increased IL-10, IL-23 and TNF-α in serum of COVID-19 patients. Furthermore, a binary logistic regression model was applied to predict death’s independent factors. Results showed that IL-10 alone or in combination with IL23 and TNF-α are strongly linked with non-survivors in COVID-19 patients. Finally, ROC curve results uncovered that IL-10, IL-23 and TNF-α were excellent predictors for prognosing COVID-19.ConclusionThe elevations of IL-10, IL-23, and TNF-α levels were seen in severe and critical cases of COVID-19 patients and their elevations were linked to the in-hospital mortality of the disease. A prediction model shows that the determination of these cytokines upon admission is important and should be done on COVID-19 patients as a way of evaluating the prognosis of the disease. COVID-19 Patients with high IL-10, IL-23, and TNF-α on admission are more likely to experience a severe form of the disease; therefore, those patients should be cautionary monitored and treated.

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C-Reactive Protein Controls IL-23 Production by Human Monocytes

Cited by 8 publications

References 64 publications

Restoration of aberrant gene expression of monocytes in systemic lupus erythematosus via a combined transcriptome-reversal and network-based drug repurposing strategy

Restoration of aberrant gene expression of monocytes in systemic lupus erythematosus via a combined transcriptome-reversal and network-based drug repurposing strategy

Cytokine Profile in Patients With Maturity-onset Diabetes of the Young (MODY)

Serum IL-23, IL-10, and TNF-α predict in-hospital mortality in COVID-19 patients

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