Regulatory effect of SOCS on NF-kappaB activity in murine monocytes/macrophages

The suppressor of cytokine signaling (SOCS) group of proteins has been implicated in regulation of various cytokine signaling and in a negative crosstalk between distinct signaling pathways. Interleukin-10 (IL-10) and LPS were known to induce expression of SOCS-3 in neutrophils and monocytes/macrophages. IL-10 was also reported to inhibit a proinflammatory signal-induced NF-kappaB activation in monocytes and peripheral T lymphocytes. The effects of increased SOCS-3 expression upon IL-10 regulation of NF-kappaB activation have not yet been demonstrated. Here we examined the effects of SOCS-3 on NF-kappaB activity. SOCS-3 did not induce any alterations in NF-kappaB activity induced by LPS or TNF-alpha. However, it enhanced RelA-dependent kappaB promoter activity when cotransfected with RelA. Similar results were observed with SOCS-1. In contrast, SOCS-2 did not show any regulatory effects on RelA activity. Analysis of C-terminal truncation mutants of SOCS-1 and SOCS-3 demonstrated that the SOCS box and its N-terminal region, a less well-conserved linker region were important for SOCS-3 activation of RelA. In contrast, the SOCS box itself was critical for SOCS-1 to activate RelA. These results suggest that SOCS proteins can enhance the effects of NF-kappaB/Rel proteins, and therefore, further modulate immune and inflammatory responses.     

Soluble MICA and a MICA Variation as Possible Prognostic Biomarkers for HBV-Induced Hepatocellular Carcinoma

MHC class I polypeptide-related chain A (MICA) molecule is induced in response to viral infection and various types of stress. We recently reported that a single nucleotide polymorphism (SNP) rs2596542 located in the MICA promoter region was significantly associated with the risk for hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) and also with serum levels of soluble MICA (sMICA). In this study, we focused on the possible involvement of MICA in liver carcinogenesis related to hepatitis B virus (HBV) infection and examined correlation between the MICA polymorphism and the serum sMICA levels in HBV-induced HCC patients. The genetic association analysis revealed a nominal association with an SNP rs2596542; a G allele was considered to increase the risk of HBV-induced HCC (P = 0.029 with odds ratio of 1.19). We also found a significant elevation of sMICA in HBV-induced HCC cases. Moreover, a G allele of SNP rs2596542 was significantly associated with increased sMICA levels (P = 0.009). Interestingly, HCC patients with the high serum level of sMICA (>5 pg/ml) exhibited poorer prognosis than those with the low serum level of sMICA (≤5 pg/ml) (P = 0.008). Thus, our results highlight the importance of MICA genetic variations and the significance of sMICA as a predictive biomarker for HBV-induced HCC.     

A variant in the LRRFIP1 gene is associated with adiposity and inflammation

Inflammation is an important factor linking abdominal obesity with insulin resistance and related cardiometabolic risk. A genome‐wide association study of adiposity‐related traits performed in the Quebec Family Study (QFS) revealed that a single‐nucleotide polymorphism (SNP) in the LRRFIP1 gene (rs11680012) was associated with abdominal adiposity (P = 4.6 × 10^–6).

Objective:

The objective of this study was to assess the relationship between polymorphisms in LRRFIP1 gene and adiposity (BMI, fat mass (FM), waist circumference (WC), and computed tomography‐derived areas of total, subcutaneous and visceral abdominal adipose tissue) and markers of inflammation (C‐reactive protein (CRP) and interleukin‐6 (IL‐6)).

Design and Methods:

Using Sequenom, 16 tag SNPs in the LRRFIP1 gene, capturing 78% of the genetic variation, were genotyped in 926 participants of the QFS.

Results:

Eight SNPs (rs7575941, rs3769053, rs11689421, rs3820808, rs11680012, rs3806505, rs6739130, and rs11686141) showed evidence of association with at least two adiposity phenotypes and plasma levels of one marker of inflammation. The strongest evidence of association was observed with rs11680012, which explained 1.8–3.4% of the variance in areas of abdominal adiposity and 2.0% of the variation in CRP levels. Carriers of the rare allele of rs11680012 had ～30% more abdominal adiposity (P values between 2.7 × 10^–4 and 3.8 × 10^–6) and 75% higher CRP levels (P = 1.6 × 10^–4) than the common allele in age and sex adjusted data. Rs11680012 is a G/C SNP converting an arginine into a threonine and this amino acid substitution may potentially alter exonic splicing.

Conclusion:

This gene may therefore represent a potential interesting target to investigate in further functional studies on adiposity and inflammation.     

Genetic Variation in NFKB1 and NFKBIA and Susceptibility to Coronary Artery Disease in a Chinese Uygur Population

Objectives

Coronary artery disease (CAD) is the most common chronic inflammatory disease worldwide. NF-κB, a central regulator of inflammation, is involved in various inflammatory diseases. The aim of this study was to investigate the association between NFKB1 and NFKBIA polymorphisms and the susceptibility to CAD and their impact on plasma levels of IL-6 in a Chinese Uygur population.

Methods

We genotyped NFKB1-94ins/del ATTG (rs28362491) and NFKBIA3’ UTR A/G (rs696) using TaqMan SNP genotyping assays in 960 Uygur CAD cases and Uygur 1060 CAD-negtive controls. IL-6 plasma levels were measured in 360 stable angina pectoris (SAP) cases and 360 controls using ELISA method.

Results

There was no significant difference in the distribution of the genotypes and alleles of rs696 polymorphism in CAD cases and controls. Significant difference in the frequency of genotypes (P = 0.001) and alleles (P = 0.001) of rs28362491 polymorphism was observed in CAD cases compared to controls. In multivariate logistic regression analysis, SNP rs28362491 was consistently associated with CAD risk in a recessive model after adjustment for cardiovascular risk factors (OR = 1.581, 95% CI 1.222 to 2.046, P<0.001). SAP cases had significantly higher plasma levels of IL-6 compared to controls (P<0.001). General linear model analysis showed rs28362491 was independently associated with increased IL-6 levels by analyses of a recessive model (P<0.001) after adjustment for covariates.

Conclusions

Our study indicates that NFKB1-94 ins/del ATTG polymorphism may play a role in CAD susceptibility in Chinese Uygur population and is functionally associated with IL-6 expression, suggesting a mechanistic link between NFKB1-94 ins/del ATTG polymorphism and CAD susceptibility.