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Noncanonical NF-κB Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF Agents.

ABSTRACT: Objectives: Targeting tumor necrosis factor (TNF) with biologic agents, such as infliximab and adalimumab, is a widely used and effective therapeutic strategy in inflammatory bowel disease (IBD). Unfortunately, a significant number of patients fail to respond or lose response over time to these agents. Previous studies have defined multiple complex roles for canonical NF-κB signaling in the pathogenesis of IBD. However, preliminary evidence suggests that the lesser defined noncanonical NF-κB signaling pathway also contributes to disease pathogenesis and response to anti-TNF agents. The objective of this study was to evaluate this hypothesis in Crohn's disease (CD) and ulcerative colitis (UC) patients. Design: A total of 27 subjects with IBD (19 with CD and 8 with UC) and 15 control subjects were tested. Clinical criteria, patient history, and endoscopic disease activity were factors used to categorize patients and define therapeutic response. Biopsy specimens were collected during colonoscopy and expression was determined for 88 target genes known to be associated with noncanonical NF-κB signaling and IBD. Results: Noncanonical NF-κB signaling was significantly upregulated in IBD patients and was associated with increased gastrointestinal inflammation, epithelial cell death, lymphocyte migration, and Nod-like receptor signaling. Furthermore, noncanonical NF-κB signaling was further upregulated in patients unresponsive to anti-TNF agents and was suppressed in responsive patients. MAP3K14, NFKB2, CCL19, CXCL12, and CXCL13 were significantly dysregulated, as were genes that encode pathway regulators, such as CYLD, NLRP12, and BIRC2/3. Conclusion: Our study identifies a previously uncharacterized role for the understudied noncanonical NF-κB signaling pathway in the pathogenesis of IBD and anti-TNF therapy responsiveness. The genes and pathways identified may ultimately prove useful in IBD management and could potentially be used as biomarkers of drug response.

SUBMITTER: Nguyen VQ

PROVIDER: S-EPMC8223059 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Elevations in plasma levels of pro-inflammatory cytokines and C-reactive protein (CRP) in patient blood have been associated with impairments in cognitive abilities and more severe psychiatric symptoms in people with schizophrenia. The transcription factor nuclear factor kappa B (NF-κB) regulates the gene expression of pro-inflammatory factors whose protein products trigger CRP release. NF-κB activation pathway mRNAs are increased in the brain in schizophrenia and are strongly related to neuroinflammation. Thus, it is likely that this central immune regulator is also dysregulated in the blood and associated with cytokine and CRP levels. We measured levels of six pro-inflammatory cytokine mRNAs and 18 mRNAs encoding NF-κB pathway members in peripheral blood leukocytes from 87 people with schizophrenia and 83 healthy control subjects. We then assessed the relationships between the alterations in NF-κB pathway genes, pro-inflammatory cytokine and CRP levels, psychiatric symptoms and cognition in people with schizophrenia. IL-1β and IFN-γ mRNAs were increased in patients compared to controls (both p < 0.001), while IL-6, IL-8, IL-18, and TNF-α mRNAs did not differ. Recursive two-step cluster analysis revealed that high levels of IL-1β mRNA and high levels of plasma CRP defined 'high inflammation' individuals in our cohort, and a higher proportion of people with schizophrenia were identified as displaying 'high inflammation' compared to controls using this method (p = 0.03). Overall, leukocyte expression of the NF-κB-activating receptors, TLR4 and TNFR2, and the NF-κB subunit, RelB, was increased in people with schizophrenia compared to healthy control subjects (all p < 0.01), while NF-κB-inducing kinase mRNAs IKKβ and NIK were downregulated in patients (all p < 0.05). We found that elevations in TLR4 and RelB appear more related to inflammatory status than to a diagnosis of schizophrenia, but changes in TNFR2 occur in both the high and low inflammation patients (but were exaggerated in high inflammation patients). Further, decreased leukocyte expression of IKKβ and NIK mRNAs was unique to high inflammation patients, which may represent schizophrenia-specific dysregulation of NF-κB that gives rise to peripheral inflammation in a subset of patients.

Project description:Utilization trends and health effects of infliximab and adalimumab in inflammatory bowel disease (IBD) are incompletely understood. We aimed to describe utilization trends of these 2 anti-tumor necrosis factor (TNF) agents, determine the correlation between utilization with rates of hospitalization and surgery and describe differences in use between adults and children.Longitudinal data were analyzed for drug utilization, hospitalization, and abdominal surgery. Descriptive statistics were used to show trends, and utilization quotients were compared for standardization. Multivariate logistic regression analysis assessed the association between drug use and rates of hospitalization and surgery.Four hundred thirty-eight pediatric and 2514 adult patients with IBD generated a total of 51,882 inpatient and outpatient encounters, representing 1185 Crohn's disease, 1531 ulcerative colitis, and 236 indeterminate colitis patients. From 2007 through 2012, utilization quotients declined for hospitalization but remained unchanged for surgery; adalimumab saw a 3-fold increase, despite continued dominance of infliximab. Median band and mean fitted plots showed downward hospitalization trends from 2006 to 2012. Utilization of infliximab peaked in 2008, Q4 with gradual decline to 2012, Q2; and adalimumab showed moderate increased utilization since 2007, Q1. Use of infliximab (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.70-0.83) and adalimumab (OR, 0.79; 95% CI, 0.72-0.87) was associated with decreased hospitalization risk but not associated with reduced abdominal surgery risk. Children had increased hospitalization (OR, 2.68; 95% CI, 2.49-2.88) but decreased risk for abdominal surgery (OR, 0.57; 95% CI, 0.46-0.70).Current infliximab use remains substantially greater than adalimumab use, despite recent increased use of adalimumab. Although trends for hospitalization for IBD are decreasing, it is not reflected in abdominal surgery rates in a tertiary IBD referral center.

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Noncanonical NF-κB Signaling Upregulation in Inflammatory Bowel Disease Patients is Associated With Loss of Response to Anti-TNF Agents.

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