Recent studies indicate that several Toll-like receptors (TLRs) are implicated in recognizing viral structures and instigating immune responses against viral infections. The aim of this study is to examine the expression of TLRs and proinflammatory cytokines in viral skin diseases such as verruca vulgaris (VV) and molluscum contagiosum (MC). Reverse transcription-polymerase chain reaction and immunostaining of skin samples were performed to determine the expression of specific antiviral and proinflammatory cytokines as well as 5 TLRs (TLR2, 3, 4, 7, and 9). In normal human skin, TLR2, 4, and 7 mRNA was constitutively expressed, whereas little TLR3 and 9 mRNA was detected. Compared to normal skin (NS), TLR3 and 9 mRNA was clearly expressed in VV and MC specimens. Likewise, immunohistochemistry indicated that keratinocytes in NS constitutively expressed TLR2, 4, and 7; however, TLR3 was rarely detected and TLR9 was only weakly expressed, whereas 5 TLRs were all strongly expressed on the epidermal keratinocytes of VV and MC lesions. In addition, the mRNA expression of IFN-beta and TNF-alpha was upregulated in the VV and MC samples. Immunohistochemistry indicated that IFN-beta and TNF-alpha were predominately localized in the granular layer in the VV lesions and adjacent to the MC bodies. Our results indicated that VV and MC skin lesions expressed TLR3 and 9 in addition to IFN-beta and TNF-alpha. These viral-induced proinflammatory cytokines may play a pivotal role in cutaneous innate immune responses.
Cytokines/metabolism ; *Gene Expression Regulation ; Humans ; Immunohistochemistry/methods ; Inflammation ; Interferon-beta/biosynthesis ; Keratinocytes/cytology ; Models, Biological ; Molluscum Contagiosum/*metabolism ; Toll-Like Receptor 3/biosynthesis ; Toll-Like Receptor 9/biosynthesis ; Toll-Like Receptors/*biosynthesis ; Tumor Necrosis Factor-alpha/biosynthesis ; Warts/*metabolism

BACKGROUND: Interferon-gamma (IFN-gamma) is essential in the immune response to mycobacterial infections, and a complete or partial deficiency in the IFN-gamma receptor 1 (IFNgammaR1) or the IFN-gamma receptor 2 (IFNgammaR2) have been reported to confer susceptibility to a disseminated infection with nontuberculous mycobacteria. However, similar mutations in the IFN-gamma receptor have not been specifically examined in the patients with clinical tuberculosis. METHODS: This study searched for mutations in the IFN-gamma receptor gene that resulted in a partial IFN-gamma receptor deficiency in six patients with disseminated tuberculosis. The previously identified IFNgammaR1 and IFNgammaR2 coding regions were sequenced after amplification. RESULTS: There was no partial IFNgammaR1 deficiency including a homozygous recessive missense mutation causing an amino-acid substitution in the extracellular domain of the receptor (I87T) and a hotspot for small deletions (818delT, 818del4, 818insA) found in any of the patients. In addition, a partial IFNgammaR2 deficiency of the homozygous missense mutation (R114C) was not found in any of the patients. CONCLUSION: Genetic defects causing a partial IFN-gamma receptor deficiency were not identified in our patients with disseminated tuberculosis.
Clinical Coding ; Genetic Predisposition to Disease ; Humans ; Interferon-gamma* ; Mutation, Missense ; Nontuberculous Mycobacteria ; Point Mutation ; Receptors, Interferon ; Tuberculosis*

To acquire epidemiological data on the bovine viral diarrhea virus (BVDV) and identify cattle persistently infected (PI) with this virus, 4,327 samples from Holstein dairy cows were screened over a four-year period in Beijing, China. Eighteen BVD viruses were isolated, 12 from PI cattle. Based on genetic analysis of their 5'-untranslated region (5'-UTR), the 18 isolates were assigned to subgenotype BVDV-1m, 1a, 1d, 1q, and 1b. To investigate the innate immune responses in the peripheral-blood mononuclear cells of PI cattle, the expression of Toll-like receptors (TLRs), RIG-I-like receptors, interferon-alpha (IFN-alpha), IFN-beta, myxovirus (influenza virus) resistance 1 (MX1), and interferon stimulatory gene 15 (ISG15) was assessed by qPCR. When compared with healthy cattle, the expression of TLR-7, IFN-alpha, and IFN-beta mRNA was downregulated, but the expression of MX1 and ISG-15 mRNA was upregulated in PI cattle. Immunoblotting analysis revealed that the expression of interferon regulatory factor 3 (IRF-3) and IRF-7 was lower in PI cattle than in healthy cattle. Thus, BVDV-1m and 1a are the predominant subgenotypes in the Beijing region, and the strains are highly divergent. Our findings also suggest that the TLR-7/IRF-7 signaling pathway plays a role in evasion of host restriction by BVDV.
Animals ; Cattle* ; China* ; Diarrhea* ; Immunity, Innate* ; Immunoblotting ; Interferon Regulatory Factor-3 ; Interferon-alpha ; Interferons ; Orthomyxoviridae ; RNA, Messenger ; Toll-Like Receptors

BACKGROUNDIt has been known that intra-cellular immunity is important for defense against viral infections and this function lies with interferon gamma (INF-gamma). Here we evaluated the role of IFN-gamma system in the pathogenesis of chronic hepatitis C (CHC).

METHODSThe levels of interferon gamma receptor alpha (IFNGR alpha) on the peripheral lymphocyte membrane were assayed with flow cytometry. The plasma concentrations of the cytokines IFN-gamma and IL-10 in CHC patients and normal controls were assayed by enzyme-linked-immunosorbent assay (ELISA). The samples were collected randomly from Xinjiang Autonomous Region, Zhejiang and the northern regions of Jiangsu Province in China.

RESULTSThe levels of IFNGR alpha in CHC patients were significantly lower than that of normal controls (NC), especially among patients during the stable stage (P < 0.001), whereas there were no significant differences between CHC in active and stable stages. Among the patients of the three regions, there were no significant differences between patients from Xinjiang and Zhejiang provinces, but both had statistically significant difference compared with the patients from Jiangsu Province (P < 0.001). Plasma IFN-gamma and IL-10 concentrations in CHC patients decreased significantly, IFN-gamma in particular, but there were no significant differences in these levels between various stages of the disease. The IFN-gamma/IL-10 (Th1/Th2) ratio in patients was reversed.

CONCLUSIONThere may be defects in the IFN-gamma system in chronic HCV infected subjects and a low immune response, which may play an important role in the persistence of HCV infection.

Adolescent ; Adult ; Aged ; Child ; Female ; Hepatitis C, Chronic ; blood ; immunology ; Humans ; Interferon-gamma ; blood ; Male ; Middle Aged ; Receptors, Interferon ; blood

OBJECTIVETo study the possible differences in the interferon gamma receptor (IFN-gamma R1) response among a variety of clinical types in patients with chronic hepatitis B (CHB) and implications in pathogenesis.

METHODSThe serum level of IFN-gamma and the expression level of IFN-gamma R1 in peripheral leucocytes, from 53 CHB patients, were examined by ELISA and flow cytometry respectively, which were compared with the baseline levels of 15 healthy controls and were performed correlation analysis with alanine aminotransferase (ALT), total bilirubin (TBil) in serum and morphological change in hepatic tissues.

RESULTSThe results showed that the level of IFN-gamma R1 (28.89% 11.77%) expressed on the membranes of lymphocytes in CHB patients, which correlated with liver inflammation (r=0.621, P<0.01) and serum TBil level (r=0.575, P<0.01), was much higher than that (9.23% 1.30%) of the healthy controls (Z=3.988, P<0.05), and no obvious difference on the membranes of leucocytes. The serum levels of IFN-gamma in patients with cirrhosis and severe hepatitis were higher than those of healthy controls. And the two was no difference from each other, but the standard deviation in each group was relatively large.

CONCLUSIONThese findings suggest that the IFN-gamma signal transduction pathway is modulated through up-regulating the expression of IFN-gamma R1 on the membranes of lymphocytes, which takes part in the immuno-pathogenesis in CHB patients.

Adult ; Aged ; Female ; Hepatitis B, Chronic ; immunology ; Humans ; Interferon-gamma ; blood ; Lymphocytes ; chemistry ; Male ; Middle Aged ; Receptors, Interferon ; blood

Type 1 Interferons (T1 IFN) play a pivotal role in innate immune responses against viral infection. Recently, this anti-viral cytokines are shown to be induced during bacterial infections via activation of various pattern recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, or NOD-like receptors. Signaling mediators such as MyD88, TRIF, MAVS, STING, or RIP2 of the receptor signaling pathways are also involved in T1 IFN responses depending on the bacterial species and their ligands. However, role of T1 IFN in anti-bacterial immunity is still obscure and its effect on immunological pathogenesis during bacterial infection has been controversial. It has been reported that T1 IFN could provide protective effect on several bacterial infections but it also aggravates pathogenic situation during some intracellular pathogens or secondary bacterial infection after respiratory viral infection. Here, we summarize recent findings how T1 IFN is induced by various bacterial pathogens and discuss the potential effect of T1 IFN responses on immune responses against bacterial infection.
Bacterial Infections* ; Bites and Stings ; Cytokines ; Immunity, Innate ; Interferon Type I* ; Interferons ; Ligands ; Receptors, Pattern Recognition ; Signal Transduction ; Toll-Like Receptors

BACKGROUNDGenetic variations in the interferon-gamma (IFN-γ) receptor 1 gene (IFNGR1) may contribute to tuberculosis (TB) risk in different populations. Many studies have investigated the relationship between IFNGR1 56C/T polymorphism and the susceptibility to TB, but have yielded conflicting results. A comprehensive meta-analysis is needed to provide a more accurate estimation of the relationship between them.

METHODSA literature search based on a combination of manual and computer-based methods was conducted on four English databases (PubMed, Science Direct, SpringerLink, and EBSCO) and three Chinese databases (Wanfang, CQVIP, and Chinese National Knowledge Infrastructure databases). Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using either the fixed-effects model or the random-effects model for different genetic models based on the heterogeneity examination.

RESULTSA total of six studies comprising 1 497 confirmed TB cases and 1 802 controls were included in this meta-analysis. Overall, no significant association was observed between IFNGR1 -56C/T polymorphism and TB susceptibility (C vs. T, OR = 0.90, 95% CI 0.69-1.17; CC vs. TT, OR = 0.87, 95% CI 0.65-1.18; TC vs. TT, OR = 1.031, 95% CI 0.872-1.219; CC+TC vs. TT, OR = 0.89, 95% CI 0.64-1.26; CC vs. TC+TT, OR = 0.92, 95% CI 0.66-1.29). In subgroup analysis, a significant association was found in the dominant model (CC+TC vs. TT, OR = 1.24, 95% CI 1.02-1.51) in Africans, but not in Asians or Caucasians.

CONCLUSIONSOur meta-analysis did not provide enough powerful evidence to identify a significant association between IFNGR1 -56C/T polymorphism and TB susceptibility in the overall population. In subgroup analysis, it indicates that IFNGR1 -56C/T is possibly associated with increased TB risk in Africans, but not in Asians or Caucasians. However, larger sample size and better-designed case-control studies are needed to validate these findings.

Genetic Predisposition to Disease ; genetics ; Humans ; Polymorphism, Single Nucleotide ; genetics ; Receptors, Interferon ; genetics ; Tuberculosis ; genetics

Toll-like receptor 9 binds to DNA from bacteria or viruses and activates a signaling pathway that leads to the induction of proinflammatory cytokines and type I interferon. Adaptor complex AP-3 was required for TLR9 trafficking and the production of type I interferon but not for proinflammatory cytokines. This suggests that TLR9 signaling is regulated by the subcellular localization of the receptor.
Bacteria ; Cytokines ; DNA ; Interferon Type I ; Toll-Like Receptor 9 ; Toll-Like Receptors

Genetic Predisposition to Disease ; Humans ; Interleukin-12 Subunit p40 ; physiology ; Receptors, Interferon ; physiology ; Receptors, Interleukin-12 ; physiology ; Toll-Like Receptors ; physiology ; Tuberculosis ; genetics ; immunology

PURPOSE: As neoplasia is the result of unbalanced cell growth and cell death, alternations in the growth control pathway including the immunity within the individual host-tumor relationship has been attributed to the development of breast cancer. Interferon(IFN)-gamma based immunity was recently reported to have an antitumor effect and some new methods to assess the state of interferon-gamma based immunity have been introduced. Interferon regulatory factor(IRF)-1 and interferon regulatory factor(IRF)-2 are transcriptional factors that mediate the effects of Interferon-gamma. It was suggested that the loss of IRF-1 expression is associated with the loss of tumor suppression and the development of IRF-2 expression is associated with oncogenic activation. Thus, we studied the significances of the IRF-1 and IRF-2 expressions as they are related with some clinicopathological parameters to determine the biological behavior of breast cancer including the menopausal status, tumor size, lymph node status, histologic grade, the expression of steroid receptors, the expression of c-erb B2 oncoprotein and the expression of p53 protein. METHODS: Formalin-fixed paraffin embedded specimens from 82 patients with invasive ductal carcinoma were used to evaluate the expression of IRF-1 and IRF-2 by performing immunohistochemical staining with using an avidin-biotin-peroxidase complex technique. RESULTS: The expression of IRF-1 was observed in 80.5 % of the study group. However, the expression of IRF-1 did not show any correlation with menopausal status, tumor size, histologic grade, the expression of steroid receptors, the expression of c-erb B2 oncoprotein and the p53 expression. Only lymph node metastasis showed a decreasing tendency of IRF-1 expression, but this was without statistical significance (p=0.075). The expression of IRF-2 was observed in 58.5% of the study group and it did not show any significant relationship with any of the above mentioned clinicopathological parameters. CONCLUSION: This study suggests that the expression of IRF-1 and IRF-2 does not affect the previously established parameters for determining such biological behaviors of breast cancer as the tumor size, lymph node metastasis, the histologic grade, the expression of steroid receptors, the expression of c-erb B2 and the expression of p53. In spite of these results, We'd like to recommend that another study be done to evaluate the role of IRF-1 and IRF-2 for the proper selection of the patients who are suitable for immunotherapy.
Breast Neoplasms* ; Breast* ; Carcinoma, Ductal ; Cell Death ; Humans ; Immunotherapy ; Interferon Regulatory Factors* ; Interferon-gamma ; Interferons* ; Lymph Nodes ; Neoplasm Metastasis ; Paraffin ; Receptors, Steroid