Cytokine and apoptosis gene polymorphisms influence the outcome of hepatitis C virus infection

BACKGROUND:Hepatitis C virus (HCV) infection is thought to be chronic and the factors leading to viral clearance or persistence are poorly understood.This study was undertaken to investigate the possibility of a significant relationship between the spontaneous clearance or the persistence of hepatitis C virus (HCV) infection and cytokine and apoptosis gene polymorphisms in Tunisian patients on hemodialysis.METHODS:Polymorphisms of the genes IL-1 (-889 IL-1α,-511 and +3954 IL-1β,IL-1Ra),IL-18 (-137 and-607),IL-12 (-1188) and Apo1/Fas (-670) were determined by PCR-RFLP,PCR-SSP and PCR-VNTR in 100 healthy blood donors and 100 patients infected with HCV and undergoing hemodialysis.The patients were classified into two groups:G1 consisted of 76 active chronic hepatitis patients (positive for HCV RNA) and G2 consisted of 24 hemodialysed patients who spontaneously eliminated the virus (negative for HCV RNA).RESULTS:The frequency of genotype association [-137GC/-607CA] IL-18 was higher in G2 (41.7%) than in G1 (15.8%) (P=0.008;OR=0.26;95% CI,0.10-0.73).We also found a higher frequency of the AA genotype of the Apo1/Fas gene in G2 (41.6%) than in G1 (17.5%) (P=0.026;OR=3.49;95% CI,1.13-10.69).Adjustment for known covariate factors (age,gender and genotype) confirmed these univariate findings and revealed that the genotype association GC-CA of the (-137 and-607) IL-18 gene and the AA genotype of the Apo1/Fas gene were associated with the clearance of HCV (P=0.041 and 0.017,respectively).CONCLUSION:The two genotypes GC-CA of the (-137 and-607) IL-18 polymorphism and the AA genotype of the Apo1/Fas gene influence the outcome of HCV infection in Tunisian patients on hemodialysis.

Cytokine gene polymorphisms and graft-versus-host disease in children after matched sibling hematopoietic stem cell transplantation:a single-center experience

Various polymorphisms in cytokine genes have recently been investigated as candidate risk factors in allogeneic hematopoetic stem cell transplantation(allo-HSCT).We retrospectively analyzed specific polymorphisms in genes for interleukin(IL)-10,IL-6,tumor-necrosis factor alpha(TNF-α)and interferon gamma(IFN-c)in a pediatric cohort of 57 histocompatibility leucocyte antigen(HLA)-identical sibling myeloablative transplants.Both recipient and donor genotypes were tested for association with graft-versus-host disease(GVHD)by statistical methods including Cox regression analysis.We found a significant association between the IL-10 promoter haplotype polymorphisms at positions-1082,-819 and-592 with the occurrence of severe(grades Ⅲ–Ⅳ)acute GVHD(aGVHD).Recipients with the haplotype GCC had a statistically significant decreased risk of severe aGVHD(hazard risk(HR)50.20,95% confidence interval(CI):0.06–0.67)in comparison with patients with other IL-10 haplotypes(P50.008).Transplant-related mortality at 1 year was significantly lower in recipients with this haplotype(HR50.17,95% CI:0.012–0.320)versus other IL-10 haplotypes(P=0.03),whereas overall survival was not influenced by IL-10 haplotype polymorphisms.In multivariate analysis,the presence of the IL-10 GCC haplotype was found as the only variable associated with a statistically significant decreased hazard of severe aGVHD development(P=0.02,HR50.21,95% CI:0.05–0.78).These results suggest that pediatric patients possessing the IL-10 GCC haplotype may be protected from the occurrence of severe aGVHD in the setting of matched sibling HSCT.

Predominant expression of Th1-type cytokines in primary hepatic cancer and adjacent liver tissues

BACKGROUND: Research has revealed a shift towards Th2 in many types of malignant tumor, but the state of Th1/Th2 is not clear in patients with primary hepatic cancer (PHC). This study was designed to determine the expression of Th1- versus Th2-type cytokines in primary hepatic cancer and the adjacent liver tissue in order to provide evidence for treatment of the Th1/Th2 shift. METHODS: Samples were collected from 11 patients with PHC. The gene expression of Th1/Th2 cytokines was detected by reverse transcriptase polymerase chain reaction (RT-PCR) using IFN-gamma and IL-2 as Th1-type cytokine genes, and IL-4 and IL-10 as Th2-type cytokine genes. RESULTS: Th1-type cytokines were expressed in 7/11 PHCs and 9/11 adjacent liver tissues, while Th0 type cytokines occurred in 4/11 PHCs and 2/11 adjacent liver tissues. CONCLUSION: Th1-type cytokines are expressed predominantly in primary hepatic cancer and the adjacent liver tissue.

Th1 cytokine-based immunotherapy for cancer

Cytokine-based immunotherapy is executed by harnessing cytokines to activate the immune system to suppress tumors. Th1-type cytokines including IL-1, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor are potent stimulators of Th1 differentiation and Th1-based antitumor response. Many preclinical studies demonstrated the antitumor effects of Th1 cytokines but their clinical efficacy is limited.Multiple factors influence the efficacy of immunotherapy for tumors. For instance immunosuppressive cells in the tumor microenvironment can produce inhibitory cytokines which suppress antitumor immune response. Most studies on cytokine immunotherapy focused on how to boost Th1 response; many studies combined cytokine-based therapy with other treatments to reverse immunosuppression in tumor microenvironment.In addition, cytokines have pleiotropic functions and some cytokines show paradoxical activities under different settings.Better understanding the physiological and pathological functions of cytokines helps clinicians to design Th1-based cancer therapy in clinical practice.

Analysis of Association between Interleukin-6 (IL6), Interleukin-13 (IL13) and Tumor Necrosis Factor-Alpha (TNF-alpha) Gene Polymorphisms and Genetic Susceptibility of Rheumatoid Arthritis in Kuwaiti Arab

Background: Rheumatoid arthritis (RA) is a common autoimmune disease in which a combination of risk alleles from different susceptibility genes predisposes the patients to develop clinical symptoms following exposure to environmental factors. RA is a chronic and progressive disease characterized by synovial inflammation that results in destruction in the affected joints and severe problems in individual’s mobility. Several immune-related risk factors have been associated with RA, these include single nucleotide polymorphisms (SNPs) in cytokine genes. The impact of these cytokine gene polymorphisms is due to their association either with elevated serum levels and/or variations in their serum levels are associated with disease-onset and progression. The objective of this study was to investigate the role of Interleukin-6 (IL6), Interleukin-13 (IL13) and Tumor necrosis factor-alpha (TNF-alpha) gene polymorphisms in genetic susceptibility of RA in Kuwaiti patients. Methods: We have determined the genotypes of IL6 gene (-174G/C;rs1800795), IL13 gene (R130Q;rs20541) and TNF-alpha gene (-308A/G' rs1800629) polymorphisms in 192 Kuwaiti patients with RA and compared it to that in 104 healthy controls. The diagnosis of RA was based on the American College of Rheumatology (ACR) classification criteria. The genotypes for IL6, IL13 and TNF-alpha gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods and confirmed by DNA sequencing. Results: The frequency of IL6 gene (-174G/C;rs1800795) and TNF-alpha gene (-308A/G' rs1800629) polymorphisms manifested a statistically significant difference between Kuwaiti RA patients and controls (P = 0.02 and 0.002 respectively). In contrast, the frequency of IL13 gene (R130Q;rs20541) polymorphism did not show a significant difference between Kuwaiti RA patients and controls. Conclusions: Our data showed an association of two cytokine gene polymorphisms (i.e. IL6 gene -174G/C;rs1800795 polymorphism, and TNF-alpha gene -308A/G, rs1800629 polymorphism) with RA in Kuwaiti patients highlighting their significant contribution in genetic susceptibility of this chronic disease possibly along with other factors.

Time-dependent gene expression analysis after mouse skeletal muscle contusion

Background:Though the mechanisms of skeletal muscle regeneration are deeply understood,those involved in muscle contusion,one of the most common muscle injuries in sports medicine clinics,are not.The objective of this study is to explore the mechanisms involved in muscle regeneration after contusion injury.Methods:In this study,a total of 72 mice were used.Eight of them were randomly chosen for the control group,while the rest were subjected to muscle contusion.Subsequently,their gastrocnemius muscles were harvested at different time points.The changes in muscle morphology were assessed by hematoxylin and eosin(HE) stain.In addition,the gene expression was analyzed by real-time polymerase chain reaction.Results:The data showed that the expression of many genes,i.e.,specific markers of immune cells and satellite cells,regulatory factors for muscle regeneration,cytokines,and chemokines,increased in the early stages of recovery,especially in the first 3 days.Furthermore,there were strict rules in the expression of these genes.However,almost all the genes returned to normal at 14 days post-injury.Conclusion:The sequence of immune cells invaded after muscle contusion was neutrophils,M1 macrophages and M2 macrophages.Some CC(CCL2,CCL3,and CCL4) and CXC(CXCL10) chemokines may be involved in the chemotaxis of these immune cells.HGF may be the primary factor to activate the satellite cells after muscle contusion.Moreover,2 weeks are needed to recover when acute contusion happens as used in this study.

Applications of Nanobiomaterials in the Therapy and Imaging of Acute Liver Failure

Acute liver failure(ALF),a fatal clinical disease featured with overwhelming hepatocyte necrosis,is a grand challenge in global health.However,a satisfactory therapeutic option for curing ALF is still absent,other than liver transplantation.Nanobiomaterials are currently being developed for the diagnosis and treatment of ALF.The liver can sequester most of nanoparticles from blood circulation,which becomes an intrinsic superiority for nanobiomaterials targeting hepatic diseases.Nanobiomaterials can enhance the bioavailability of free drugs,thereby significantly improving the therapeutic effects in ALF.Nanobiomaterials can also increase the liver accumulation of therapeutic agents and enable more effective targeting of the liver or specific liver cells.In addition,stimuli-responsive,optical,or magnetic nanomaterials exhibit great potential in the therapeutical,diagnostic,and imaging applications in ALF.Therefore,therapeutic agents in combination with nanobiomaterials increase the specificity of ALF therapy,diminish adverse systemic effects,and offer a multifunctional theranostic platform.Nanobiomaterial holds excellent significance and prospects in ALF theranostics.In this review,we summarize the therapeutic mechanisms and targeting strategies of various nanobiomaterials in ALF.We highlight recent developments of diverse nanomedicines for ALF therapy,diagnosis,and imaging.Furthermore,the challenges and future perspectives in the theranostics of ALF are also discussed.

IL-1β: an important cytokine associated with febrile seizures?

Febrile seizures （FSs） are the most common convulsions in childhood. Studies have demonstrated a significant relationship between a history of prolonged FSs during early childhood and temporal sclerosis, which is responsible for intractable mesial temporal lobe epilepsy. It has been shown that interleukin-1β （IL-1β） is intrinsically involved in the febrile response in children and in the generation of FSs. We summarize the gene polymorphisms, changes of IL-1β levels and the putative role of IL-1β in the generation of FSs. IL-1β could play a role either in enhancing or in reducing neural excitability. If the enhancing and reducing effects are balanced, an FS does not occur. When the enhancing effect plays the leading role, an FS is generated. A mild imbalance can cause simple FSs while a severe imbalance can cause complex FSs and febrile status epilepticus. Therefore, anti-IL-1β therapy may help to treat FSs.