Arginase is involved in cervical lesions progression and severity.

BACKGROUND: Little is known about the relationship between arginase, an immunosuppressive enzyme, and cervical lesions. The present study is aimed at evaluating arginase activity in plasma and mRNA arginase isoforms expression in cervical cells of patients with abnormal cytology and identifying their relationship with Human papillomavirus (HPV) related parameters such as: HPV type, HPV circulating viral load and anti-HPV16 IgG. METHODS: This study included 77 women with cervical lesions and 95 matched controls. Arginase activity was detected by colorimetric assay. Arginase mRNA expression and HPV viral load were evaluated by quantitative real time PCR and anti-HPV16 antibodies were assessed by ELISA. RESULTS: Compared to controls, the arginase activity was higher among women with cervicitis / low grade squamous intraepithelial lesions (LSIL) (OR: 1.872, 95% CI: 0.833-4.210), and also among women with high-grade squamous intraepithelial lesions (HSIL) / squamous cell carcinoma (SCC) (OR: 3.358, 95% CI: 1.670-8.910). Compared to controls, mRNA expression was significantly upregulated in women with cervical cervicitis and SIL for ARG1, and in women with cancer lesions for ARG2. Arginase activity was positively correlated to ARG2 mRNA expression but not to ARG1. High arginase activity was associated with HPV16, high levels of HPV viral load, and low levels of anti-HPV16 antibodies. CONCLUSIONS: Our findings demonstrated that arginase activity and isoforms expression were enhanced in women with HPV-related precancerous lesions and cervical cancer. Further studies are needed to identify how arginase enzyme induces disease progression and severity.

Combined effect of pro- and anti-inflammatory cytokine gene polymorphisms on susceptibility to liver cirrhosis in Tunisian HCV-infected patients.

PURPOSE: Chronic hepatitis C progression is commonly attributed to the continuous activation of the immune response with an increased production of pro-inflammatory cytokines, leading to fibrosis and ultimately to cirrhosis. On the contrary, anti-inflammatory cytokines, mainly interleukin (IL)-10 have a modulatory effect on hepatic fibrogenesis. The association between individual polymorphisms within cytokine genes and hepatitis C outcome is often weak and non-informative. Interestingly, it has been demonstrated that a combination of specific genotypes may be a more significant and powerful approach for predicting disease risk. AIM: This study is aimed at investigating the combined effect of single nucleotide polymorphism (SNP) in IL-18 (-607C/A, -137G/C), interferon (IFN)-γ (+874T/A) and IL-10 (-1082G/A) genes on cirrhosis risk in HCV-infected patients. METHODS: Seventy-seven chronic hepatitis C Tunisian subjects were included in this study. The patients were divided into two groups: the first included 31 non-cirrhotic patients, and the second included 46 liver cirrhosis patients. IL-18 genotyping was performed using the PCR amplification and the restriction fragment length polymorphism analysis (RFLP). IFN-γ and IL-10 polymorphisms were analyzed using the allele-specific PCR (AS-PCR). RESULTS: The combined high-risk genotype (IL-18 -607C/*, IL-18 -137G/*, IFN-γ +874T/*, IL-10 -1082A/A) frequency was compared between patients with and those without cirrhosis. Individuals were classified according the number of high-risk genotypes as follows: (0-2), patients with at most two high-risk genotypes; (3-4), patients with at least three of the high-risk genotypes. The logistic regression analysis showed that patients harboring 3-4 putative high-risk genotypes have a fivefold higher risk for developing cirrhosis in comparison to those harboring at most two high-risk genotypes (OR = 5.19; 95% CI = 1.49-18.05; p = 0.009). CONCLUSION: Our study showed that the co-inheritance of IL-18, IFN-γ and IL-10 specific high-risk genotypes is associated with a greater risk for liver cirrhosis.

Combined analysis of interferon-gamma and interleukin-10 gene polymorphisms and chronic hepatitis C severity.

Today there is increasing evidence concerning the contribution of pro-/anti-inflammatory cytokine balance and genetic factors in hepatitis C pathogenesis and interindividual heterogeneity of disease outcome. In the current study, we investigated the influence of functionally described single nucleotide polymorphisms (SNPs) present in interferon-gamma (IFNgamma) and interleukin-10 (IL-10) genes, on chronic hepatitis C severity. IFNgamma (+874T/A) and IL-10 (-1082G/A) genotypes were determined in 100 hepatitis C patients with different disease severities (chronic hepatitis, n = 42, liver cirrhosis [LC], and hepatocellular carcinoma in liver cirrhosis [HCC], n = 58) and 103 healthy controls using allele-specific polymerase chain reaction. No statistical differences in allele or genotype distributions of IFNgamma and IL-10 genes were observed between patients and controls. However, some significant differences in IFNgamma genotype frequencies were observed between the two groups of patients. IFNgamma(high producer) genotypes TT and TA were significantly more common in patients with LC and HCC (odds ratio = 2.65; p = 0.019). Although IL-10 genotypic frequencies were comparable between the different clinical forms of the disease, the combination of IFNgamma(low producer) and IL-10(high producer) genotypes was significantly associated with a lower risk of LC and HCC (odds ratio = 0.21; p = 0.015). In conclusion, our findings suggest that the imbalance between the pro-inflammatory and anti-inflammatory responses mediated by polymorphisms in the IFNgamma and IL-10 genes may influence the outcome of chronic HCV infection.

Functional IL-18 promoter gene polymorphisms in Tunisian nasopharyngeal carcinoma patients.

OBJECTIVES: There is growing evidence suggesting that IL-18 levels may affect individual to virus-associated neoplasia and that single nucleotide polymorphisms (SNPs) within the gene may influence its production. In this study we wanted to know whether IL-18 polymorphisms at positions -607 C/A and -137 G/A are associated with susceptibility and/or are markers of nasopharyngeal carcinoma (NPC) prognosis. METHODS: Using the restriction fragment length polymerase chain reaction (RFLP-PCR), 163 Tunisian patients and 164 healthy controls were genotyped. RESULTS: No significant association was found between each studied polymorphism and NPC. However, we noted that the -607 A allele, which is associated with lower IL-18 production, increased the risk of advanced tumor stages (OR=3.59; P=0.017) and that this risk was more pronounced among the older patient's age at onset (OR=3.85; P=0.012). Moreover, the significant difference in CA/GG haplotype frequency distribution between young and older patients supported the idea that NPC disease has biologically different features between age sub-groups. CONCLUSION: Functional IL-18 gene polymorphisms do not influence the susceptibility to NPC in Tunisians but may contribute to disease onset and aggressiveness.