Dataset Information

Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease.

ABSTRACT: While activation of the IL-6-dependent transcription factor signal transducer and activator of transcription 3 (STAT3) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), a direct effect on mucosal gene expression and inflammation has not been shown. We hypothesized that a proinflammatory IL-6:STAT3-dependent biological network would be up regulated in pediatric-onset IBD patients, and would be associated with the severity of mucosal inflammation.Patients with pediatric-onset IBD were enrolled at diagnosis and during therapy. Serum cytokine analysis was performed using Bioplex. STAT3 phosphorylation (pSTAT3) in peripheral blood leukocytes (PBLs) was assessed by flow cytometry. Immunohistochemistry of colonic mucosa was used to localize pSTAT3 and STAT3 target genes. Microarray analysis was used to determine RNA expression profiles from colon biopsies.Circulating IL-6 was upregulated in active IBD patients at diagnosis and during therapy. STAT3 activation was increased in PB granulocytes, IL-6-stimulated CD3(+)/CD4(+) lymphocytes, and affected colon biopsies of IBD patients. The frequency of pSTAT3+ PB granulocytes and colon epithelial and lamina propria cells was highly correlated with the degree of mucosal inflammation. Microarray and Ingenuity Systems bioinformatics analysis identified IL-6:STAT3-dependent biological networks upregulated in IBD patients which control leukocyte recruitment, HLA expression, angiogenesis, and tissue remodeling.A proinflammatory IL6:STAT3 biologic network is upregulated in active pediatric IBD patients at diagnosis and during therapy. Specific targeting of this network may be effective in reducing mucosal inflammation.

SUBMITTER: Carey R

PROVIDER: S-EPMC2581837 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease.

Carey Rebecca R Jurickova Ingrid I Ballard Edgar E Bonkowski Erin E Han Xiaonan X Xu Huan H Denson Lee A LA

Inflammatory bowel diseases 20080401 4

<h4>Background</h4>While activation of the IL-6-dependent transcription factor signal transducer and activator of transcription 3 (STAT3) has been implicated in the pathogenesis of inflammatory bowel disease (IBD), a direct effect on mucosal gene expression and inflammation has not been shown. We hypothesized that a proinflammatory IL-6:STAT3-dependent biological network would be up regulated in pediatric-onset IBD patients, and would be associated with the severity of mucosal inflammation.<h4>M ...[more]

PMID: 18069684

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Project description:BackgroundThe incidence of pediatric inflammatory bowel disease (PIBD) has increased dramatically during the past decades. This implies involvement of environmental factors in etiology but lends no clues about specific agents. We evaluated clustering in time and place of residence at PIBD onset using a case-control setting with comprehensive nationwide register data.MethodsWe included all PIBD cases diagnosed at ages < 18 years during 1992-2017 (3748 cases; median age of 14.6; 2316 (58%) with ulcerative colitis (UC), 1432 with Crohn's, and 18,740 age- and sex-matched controls) and constructed complete residential histories (including coordinates) from the national database until the date of the diagnosis of the case assigned as index date for the controls. Using the coordinates of the addresses of the subjects and the diagnosis/index dates, we evaluated clustering in time and place using the Knox test. Four temporal (2, 4, 6, 12 months) and four distance (0.25, 0.5, 1, 5 km) thresholds were used, and results were calculated separately for Crohn´s disease and UC. Similar analyses were conducted using the addresses at birth and the addresses five years before the diagnosis or index date. Based on the threshold values displaying the most clustering in the Knox test, logistic regression models were built to identify whether sex, age at diagnosis or the year of diagnosis affected the probability of belonging to a cluster. To analyze clustering in time and place throughout the residential histories, we used Jacquez's Q with an open-access python program pyjacqQ.ResultsThe mean number of residencies until the index date was 2.91 for cases and 3.05 for controls (p = 0.0003). Knox test indicated residential clustering for UC with thresholds of 500 m between locations and time-period of four months (p = 0.004). In the regression analysis, sex, age at diagnosis or year of UC diagnosis did not show differences between the clustered and other cases. Jacquez Q analyses showed higher than expected frequency of clustered cases throughout residential histories (p < 10- 8).ConclusionOur findings suggest that the incidence of PIBD, especially of UC, exhibits clustering in locations of residencies over time. For the clustered cases, environmental triggers warrant future studies.

Project description:Patient activation is an important consideration for improved health outcomes in the management of chronic diseases. Limited English proficiency among patients and primary care providers has been shown to be a predictor for worse health across disease states. We aimed to determine the baseline patient activation measure (PAM) among Spanish-speaking (SP) and English-speaking (ES) pediatric patients with IBD and parents, and to describe the feasibility and efficacy of a novel peer-group education symposium designed to enhance patient activation as measured with the PAM.Two separate half-day educational symposia in either Spanish or English were presented and moderated by 2 native SP physicians. Content for each of the presentations were highly standardized and interactive, designed to address each of the activation domains (self-management, collaboration with a health care provider, maintenance of function and prevention of disease exacerbation, and appropriate access to high-quality care). Descriptive statistics were used to describe changes between pre- and postsymposium PAM trends.Eleven primarily SP and 21 ES families participated in their respective symposium. Paired pre- and post-PAM scores were available from 24 pediatric patients with IBD (8 SP, 16 ES) and 41 parents (15 SP, 26 ES). The mean age for SP and ES patients was 11.6 and 12.0 years, and female sex in 80% and 62%, respectively. Paired pre- and post-PAM scores for all participants (n?=?65) were analyzed. PAM scores uniformly increased in all 4 groups after the symposia (SP patients 59.1-70.3, P?=?0.05; SP parents 69.8-75.2, P?=?0.2; ES patients 59.9-64.0, P?=?0.08; ES parents 61.9-69.1, P?=?0.002), although only the ES-parents group had sufficient sample size (n?=?26) to achieve statistical significance. The overall cohort had an aggregate increase from pre-PAM of 62.9 (SD 14.5) to post-PAM of 69.4 (SD 13.9) (<0.001).We describe a novel peer-group educational symposium presented in Spanish and English languages to increase patient and parent activation in pediatric patients with IBD and their caregiving parents. The use of PAM to assess levels of activation appears to be feasible and effective in these groups.

Dataset Information

Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease.

Publications

Activation of an IL-6:STAT3-dependent transcriptome in pediatric-onset inflammatory bowel disease.

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