Increased expression and activation of IL-12-induced Stat4 signaling in the mucosa of ulcerative colitis patients

Department of Gastroenterology, Beijing Chaoyang Hospital, The Capital University of Medical Sciences, Beijing 100020, China.
Cellular Immunology (Impact Factor: 1.92). 09/2007; 248(2):115-20. DOI: 10.1016/j.cellimm.2007.10.003
Source: PubMed

ABSTRACT Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory diseases with unsolved pathogenesis. Imbalanced Th1/Th2 may play a role in the sustained inflammation of IBD. In China, CD is rare but the incidence of UC has been rising steadily in the last two decades. We investigated the expression of IL-12 (p40) and IFN-gamma, and the activational state of Stat4 signaling in mucosal tissues at the site of disease from 30 active UC patients in comparison with 30 healthy controls. RT-PCR analyses revealed increased mRNA expression of IL-12 (p40) but not IFN-gamma in UC patients. Western blot analyses discovered, for the first time, increased levels of constitutive Stat4 in the cytoplasm and phosphorylated Stat4 in the nucleus of mucosal cells from UC patients. We conclude that a heightened, perhaps persistent, activational state of IL-12/Stat4, and/or IL-23/Stat4 signaling may be present in active Chinese UC patients, and possibly involved in chronic inflammation in UC.

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    • "Recent studies have implicated their members’ possible involvement in the pathogenesis of IBD. For example, the expression and/or activation of interleukin 12 (IL-12) and Stat4, including phosphorylated Stat4, suggest that proinflammatory IL-12/Stat4 signalling or IL-23/Stat4 are likely candidate pathways involved in the inflammatory pathology in UC and colorectal cancer (CRC) [15–17]. Moreover, it is generally recognized that there is an increased risk of CRC in patients with UC, and the overall prevalence of manifest CRC in patients with UC is unacceptably high. "
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    ABSTRACT: Introduction Several studies have reported the relationship between the STAT4 rs7574865G > T polymorphism as a susceptibility factor to ulcerative colitis (UC). However, the results have been controversial. Therefore, we conducted this meta-analysis to obtain the most reliable estimate of the association. Material and methods PubMed, Embase and Web of Science databases were searched. Crude odds ratios (OR) with 95% confidence intervals (CI) were extracted and pooled to assess the strength of the association between the STAT4 rs7574865G > T polymorphism and risk of UC. A total of five eligible studies including 1532 cases and 3786 controls based on the search criteria were involved in this meta-analysis. Results We observed that the STAT4 rs7574865G > T polymorphism was significantly correlated with UC risk when all studies were pooled into the meta-analysis (the allele contrast model: OR = 1.13, 95% CI = 1.02–1.25; the heterozygote codominant model: OR = 1.22, 95% CI = 1.04–1.43; the dominant model: OR = 1.25, 95% CI = 1.07–1.45). In the stratified analysis by ethnicity, significant associations were observed in Spanish for the allele contrast model (OR = 1.20; 95% CI = 1.04–1.39), for the homozygote codominant model (OR = 1.57; 95% CI = 1.07–2.31), for the dominant model (OR = 1.20; 95% CI = 1.01–1.43), and for the recessive model (OR = 1.50; 95% CI = 1.03–2.19). Conclusions This meta-analysis suggests that the STAT4 rs7574865G > T polymorphism is a low-penetrant risk factor for UC, especially in Spanish.
    Archives of Medical Science 06/2014; 10(3):419-24. DOI:10.5114/aoms.2014.43735 · 2.03 Impact Factor
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    • "The signal transducer and activator of transcription 4 (STAT4) is an interesting candidate gene that may play a role in the genetic background of IBD for two principal reasons. First, STAT4 is an important player in directing T helper cells toward the Th1 and Th17 lineages, both of which are implicated in autoimmune processes, including IBD pathogenesis [13] [14] [15] [16] [17] [18] [19]. Second, recent findings suggest that the STAT4 gene may be a common genetic factor in autoimmunity [20] [21] Thus, the STAT4 gene was first associated with a genetic predisposition to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), with a single nucleotide polymorphism (SNP) of STAT4 intron 3 (rs7574865) showing the strongest effect [22] [23] [24] [25] [26]. "
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    ABSTRACT: Recently, the signal transducer and activator of transcription 4 (STAT4) gene has been associated with multiple autoimmune diseases. Interestingly, a recent work showed that the T allele of the rs7574865 STAT4 SNP was associated with inflammatory bowel disease (IBD) in a Spanish population. The aim of the present study was to reevaluate the role of the STAT4 rs7574865 polymorphism on IBD. The present case-control study included 498 Crohn's disease (CD) patients, 402 ulcerative colitis (UC) patients, and 1296 healthy matched controls. Genotyping was performed using a PCR system with a pre-developed TaqMan allelic discrimination assay for the rs7574865 STAT4 SNP. Moreover, a meta-analysis was performed with the previous work in a Spanish population and the current study, including a final sample size of 1574 IBD patients (820 with CD and 754 with UC) and 2012 healthy controls. No evidence of association was found for the current case-control study (CD: p = 0.23, OR = 0.9, 95% CI = 0.75-1.1; UC: p = 0.17, OR = 1.14, 95% CI = 0.95-1.38). However, the meta-analysis showed that the STAT4 rs7574865 T allele was significantly associated with susceptibility to UC (p = 0.012 pooled; OR = 1.20, 95% CI = 1.04-1.39) but not CD (p = 0.71 pooled; OR = 0.93, 95% CI = 0.65-1.34). Our data suggest that the rs7574865 STAT4 SNP is a genetic susceptibility variant for UC but not CD in the Spanish population.
    Human immunology 02/2010; 71(5):515-9. DOI:10.1016/j.humimm.2010.02.005 · 2.14 Impact Factor
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    • "However, it was interesting to note that Stat6 null Caco-2 cells appeared to have signiWcant constitutive mRNA expression of STAT4, which was not seen in Stat6 high HT-29 cells (Fig. 3). The expression of Stat4 is inducible by IL-12 and IL-23, and involved in proinXammatory response (Watford et al. 2004; Neurath 2007; Pang et al. 2007). The constitutive STAT4 expression in Stat6 null Caco-2 cells may be relevant to our previous Wndings that Stat6 null cells exhibited increased spontaneously apoptosis and constitutive expression of IL-12 (Galka et al. 2004; Zhang et al. 2004). "
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    ABSTRACT: PurposeTo investigate potential differences in the expression of Stat6 regulatory genes that may influence IL-4/Stat6 activities (phenotypes) in colon cancer cells. MethodsRT-PCR method was employed to examine the constitutive mRNA expression of Stat6 negative regulators SOCS-1 and SHP-1, and positive regulator PP2A in colon cancer cell lines HT-29 and Caco-2. Stat6 protein expression and nuclear phosphorylation were detected using Western blotting. ResultsCaco-2 cells carrying inactive Stat6null phenotype showed normal constitutive expression of Stat6 but decreased phosphorylation of nuclear Stat6 compared with HT-29 cells carrying active Stat6high phenotype. Stat6null Caco-2 cells expressed increased levels of mRNA and protein of SOCS-1 and SHP-1, and decreased mRNA expression of PPP2CA and PPP2CB, encoding two critical subunits of PP2A. ConclusionsConstitutively increased expression of Stat6 negative regulators SOCS-1 and SHP-1, together with decreased expression of positive regulator PP2A, may play a role in forming the inactive Stat6null phenotype in colon cancer cells.
    Journal of Cancer Research and Clinical Oncology 12/2008; 135(1):131-140. DOI:10.1007/s00432-008-0429-8 · 3.08 Impact Factor
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