Cytokine and Chemokine Gene Polymorphisms Among Ethnically Diverse North Americans With HIV-1 Infection
Chengbin WangWei SongElena LobashevskyCraig M. WilsonSteven D. DouglasJoannis MytilineosEllie E. SchoenbaumJianming TangRichard A. Kaslow
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Abstract:
Twenty-four common single nucleotide polymorphisms (SNPs) in 10 cytokine and chemokine genes were defined in 579 North Americans at high risk of HIV-1 infection due to sexual behavior and injection drug use. Among the 3 major ethnic (African-American, Hispanic/Latino, and other) groups involved, HIV-1–seropositive individuals differed significantly from ethnically matched HIV-1–seronegative individuals (odds ratios = 2.13–4.82; P = 0.003–0.05) for several SNPs and haplotypes defined at the IL4, IL4R, IL6, IL10, CCL5 (RANTES), and CXCL12 (SDF1) loci. In addition, the homozygous IL4–590T/T genotype was associated with higher (+87−131 cells/μL) CD4+ T-cell counts in HIV-1–infected and AIDS-free adolescents not receiving antiretroviral therapy (adjusted P = 0.004). No SNPs at IFNG, IL2, IL12B, TNF, or CCL2 (MCP1) showed any association with HIV-related outcomes. Additional typing for IL1A, IL1B, IL1R1, IL1RN, and TGFB1 SNPs also failed to demonstrate any influence on HIV-1 infection or virologic/immunologic control in more selected patient groups. Coupled with previous findings, our data suggest that heritable IL4 and IL10 variations may contribute to the acquisition or progression of HIV infection and that the effects of other targeted loci in the cytokine and chemokine system cannot be established unequivocally in the study populations.Keywords:
CXCL9
CCL5
CYP4A11, which is a member of the cytochrome P450 family, acts mainly as an enzyme that converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), a metabolite involved in the maintenance of cardiovascular health. Recently, it was reported that many subfamilies of CYP genes have an association with myocardial infarction (MI). The aim of the present study was to assess the association between the human CYP4A11 gene and MI, using a haplotype-based case-control study with a separate analysis of the gender groups. A total of 239 MI patients and 285 controls were genotyped for 3 single-nucleotide polymorphisms (SNPs) of the human CYP4A11 gene (rs2269231, rs1126742, rs9333025). The data obtained via haplotype-based case-control studies were assessed for 3 separate groups: total subjects, men, and women. For the total, men and women groups, the distribution of the genotypes and alleles of the 3 SNPs did not show any significant difference between the MI patients and the control subjects. For the total and the men groups, the overall distribution of the haplotypes constructed with the 3 SNPs significantly differed between the MI patients and control subjects (P < 0.001). Also, for the total and for the men, the frequency of the T-T-A haplotype constructed with the 3 SNPs was significantly lower for the MI patients than for the control subjects (both P < 0.001). The T-T-A haplotype constructed with the 3 SNPs appears to be a protective genetic marker for MI in Japanese men.
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We examined the role of interferon-γ (IFN-γ) in expression of chemokine mRNA and proteins in the brain during chronic infection with Toxoplasma gondii using BALB/c and BALB/c-background IFN-γ knockout (IFN-γ(-/-)) mice. BALB/c mice are genetically resistant to development of toxoplasmic encephalitis and establish a latent, chronic infection in the brain through IFN-γ-mediated immune responses. Amounts of mRNA for CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC, CCL2/MCP-1, CCL3/MIP-1α, and CCL5/RANTES significantly increased in the brains of wild-type mice after infection. CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES mRNA were most abundant among these chemokines. An increase in amounts of mRNA for CXCL10/IP-10, CCL2/MCP-1, CCL3/MIP-1α, and CCL5/RANTES was also observed in the brains of IFN-γ(-/-) mice after infection, although CXCL10/I-10 and CCL5/RANTES mRNA levels in infected IFN-γ(-/-) mice were significantly lower than those of infected wild-type animals. Amounts of mRNA for CXCL9/MIG and CXCL11/I-TAC remained at the basal levels in infected IFN-γ(-/-) mice. When amounts of the chemokine proteins were examined in the brain homogenates of uninfected and infected mice of both strains, large amounts of CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES were detected only in infected wild-type animals. These results indicate that CXCL9/MIG, CXCL10/IP-10, and CCL5/RANTES are the chemokines predominantly induced in the brains of genetically resistant BALB/c mice during chronic infection with T. gondii, and their expression is dependent on IFN-γ.
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Abstract We examined the role of IFN-γ in expression of chemokine mRNA and proteins in the brain during chronic infection with Toxoplasma gondii using BALB/c and BALB/c-background IFN-γ knockout (IFN-γ-/-) mice. BALB/c mice are genetically resistant to development of toxoplasmic encephalitis and establish a latent, chronic infection in the brain through IFN-γ-mediated immune responses. Amounts of mRNA for CXCL9, CXCL10, CXCL11, CCL2, CCL3, and CCL5 significantly increased in the brains of wild-type mice after infection. CXCL9, CXCL10, and CCL5 mRNA were most abundant among these chemokines. An increase in amounts of mRNA for CXCL10, CCL2, CCL3, and CCL5 was also observed in the brains of IFN-γ-/- mice after infection, although CXCL10 and CCL5 mRNA levels in infected IFN-γ-/- mice were significantly lower than those of infected wild-type animals. Amounts of mRNA for CXCL9 and CXCL11 remained at the basal levels in infected IFN-γ-/- mice. When amounts of the chemokine proteins were examined in the brain homogenates of uninfected and infected mice of both strains, large amounts of CXCL9, CXCL10, and CCL5 were detected only in infected wild-type animals. These results indicate that CXCL9, CXCL10, and CCL5 are the chemokines predominantly induced in the brains of genetically resistant BALB/c mice during chronic infection with T. gondii, and their expression is dependent on IFN-γ.
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Aims: Chemokines are inflammatory mediators during acute and chronic liver injury. The chemokine RANTES (CCL5) directs lymphocytes to inflamed tissues and directly activates hepatic stellate cells in vitro through interaction with CCR5. These functions define RANTES as an interesting target for antifibrotic therapies. We here present data defining the role of RANTES in human and murine liver fibrosis.
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Hepatic stellate cell
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Chemokines are small‐secreted proteins that stimulate the directional migration of leukocytes and thereby mediate the inflammatory process. The present study investigates the capacity of human gingival fibroblasts to produce the β chemokine Rantes/CCL5. In situ hybridization, immunohistochemistry and ELISA were used to measure the induction of Rantes/CCL5 at the mRNA and protein levels, both in unstimulated gingival fibroblasts as well as in fibroblasts treated with the proinflammatory cytokines tumor necrosis factor (TNF)α or interleukin (IL)‐1β. TNFα in different concentrations (0.1–10 ng/ml) induced Rantes/CCL5 mRNA expression and protein production in 24‐h cultures of human gingival fibroblasts. The expression of Rantes/CCL5‐mRNA and protein production, induced by TNFα, was evident at 6 h and thereafter increased continuously during the study period (24 h). IL‐1β (3–300 pg/ml) also enhanced the production of Rantes/CCL5 in gingival fibroblasts. The amount of Rantes/CCL5 induced by IL‐1β (300 pg/ml), however, was less than that induced by TNFα (10 ng/ml). The study suggests that human gingival fibroblasts, by producing the chemokine Rantes/CCL5, participate in the regulation of the host response during the inflammatory process in the periodontal tissue.
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Proinflammatory cytokine
Interleukin 8
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MicroRNAs (miRNAs) are widely involved in immune regulation during virus infection. Several studies showed that the expression of miR-146a was increased in human immunodeficiency virus type I (HIV-1)-infected cells, but the definitive function of miR-146a in HIV-1 infection remains obscure. The production of chemokine (C-C motif) ligand 5 (CCL5) in macrophages has been reported to play an important role in HIV/AIDS-associated pathogenesis. In this study, we examined the effects of miR-146a on CCL5 regulation in HIV-1-infected macrophages. Gain and loss of function studies showed that CCL5 might be one of the miR-146a targets, as miR-146a mimic reduced, while miR-146a inhibitor increased CCL5 production in HIV-1-infected macrophages. In addition, we demonstrated that miR-146a reduced CCL5-induced monocyte migration. Our study provided evidence that miR-146a targets CCL5 3' untranslated regions, downregulates its release from macrophages, and affects monocyte migration consequently. These findings drew a novel layer of posttranscriptional control of the chemokine CCL5 by miR-146a during HIV infection, which might contribute to HIV pathogenesis.
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Mediator
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Chemokines are important regulators of neuroinflammation and interact with brain endothelial cells that comprise the blood-brain barrier (BBB) to modulate their function and promote their interactions with leukocytes. Chemokines can also cross the intact BBB, which may contribute to their functions in the brain, but interactions of chemokines with the BBB in vivo are understudied. Here, we show that the chemokines C-C motif ligand 2 (CCL2) and C-C motif ligand 5 (CCL5), which have been well-studied in context of their neuroinflammatory functions, are amenable to labeling with 125I. This affords highly sensitive and quantitative detection of CCL2 and CCL5 in vivo, and allows for rapid assessment of the distribution of circulating chemokines. Multiple-time regression analysis was used to characterize chemokine transport across the mouse BBB. In untreated mice, we evaluated the brain uptake of CCL2 and CCL5 and characterized saturability of uptake and endothelial binding vs. transport. We then determined whether CCL2 and CCL5 interactions with the BBB are altered in mice treated with three doses of 3mg/kg lipopolysaccharide. Our results indicate that in addition to endothelial binding at the glycocalyx, there is uptake of both CCL5 and CCL2 into the mouse brain parenchyma. We found no significant difference in the rate of chemokine uptake in mice treated with LPS versus untreated mice. However, the 125I counts per minute (CPM) was significantly higher in the brains of LPS mice versus untreated mice brains, indicating that more radio-labelled chemokine had entered the brain after LPS-induced inflammation. In conclusion, we have found that chemokines interact with the intact BBB, and alterations in theses interactions with inflammation can be detected in vivo. As a future direction, this method can be utilized to evaluate pharmacological approaches to inhibiting BBB/chemokine interactions, which may protect against harmful neuroinflammation during neurological disease.
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Nebel D, Jönsson D, Norderyd O, Bratthall G, Nilsson B-O. Differential regulation of chemokine expression by estrogen in human periodontal ligament cells. J Periodont Res 2010; 45: 796–802. © 2010 John Wiley & Sons A/S Background and Objective: Estrogen modulates inflammatory responses, but the mechanisms involved have not yet been identified. Periodontal ligament (PDL) cells produce chemokines (a group of chemoattractant molecules that recruit leukocytes) and it has been suggested that estrogen modulates periodontal inflammation by regulating the expression of chemokines by PDL cells. Therefore, the objectives of this study were to investigate the regulation of chemokine ligand 2 [CCL2/monocyte chemoattractant protein 1 (MCP-1)], chemokine ligand 3 [CCL3/macrophage inflammatory protein-1α (MIP-1α)] and chemokine ligand 5 (CCL5/RANTES) by estrogen in human PDL cells. Material and Methods: PDL cells were obtained from the PDL of premolars, extracted for orthodontic reasons, from two boys and two girls (16 and 17 years of age). PDL cell CCL2, CCL3 and CCL5 mRNA transcripts were determined by quantitative real-time PCR. The concentrations of CCL2, CCL3 and CCL5 proteins were determined by ELISAs. Results: Treatment with 0.5 μg/mL of lipopolysaccharide (LPS, from Escherichia coli) + 100 nm 17β-estradiol (E2) for 24 h reduced the expression of CCL3 mRNA by about 40% compared to PDL cells treated with LPS alone. Attenuation of CCL3 mRNA was not associated with a decrease in CCL3 protein within 48 h, suggesting a slow turnover of the CCL3 protein. Interindividual differences in the effects of E2 on CCL5 mRNA expression were observed. E2 (100 nm) increased the expression of CCL5 by 40–60% in PDL cells derived from two subjects but reduced the expression of CCL5 by about 30% in cells from another subject. CCL2 mRNA and CCL2 protein were highly expressed, but not regulated by E2. Similar data were observed in cells obtained from both boys and girls. Conclusion: Regulation, by estrogen, of chemokine expression in PDL cells shows a complex pattern involving the down-regulation as well as the up-regulation of chemokines, suggesting that estrogen exerts both anti-inflammatory and proinflammatory effects through these mechanisms.
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