Search

T lymphocytes represent an important part of adaptive immune system undertaking different functions to regulate immune responses. CD4+ T cells are the most important activator cells in inflammatory conditions. Depending on the type of induced cells and inflamed sites, expression and activity of different subtypes of helper T cells are changed. Recent studies have confirmed the existence of a new subset of helper T lymphocytes called Th9. Naive T cells can differentiate into Th9 subtypes if they are exposed simultaneously by interleukin (IL) 4 and transforming growth factor β and also secondary activation of a complicated network of transcription factors such as interferon regulatory factor 4 (IRF4) and Smads which are essential for adequate induction of this phenotype. Th9 cells specifically produce interleukin 9 and their probable roles in promoting intestinal inflammation are being investigated in human subjects and experimental models of ulcerative colitis (UC). Recently, infiltration of Th9 cells, overexpression of IL-9, and certain genes associated with Th9 differentiation have been demonstrated in inflammatory microenvironment of UC. Intestinal oversecretion of IL-9 protein is likely to break down epithelial barriers and compromise tolerance to certain commensal microorganisms which leads to inflammation. Th9 pathogenicity has not yet been adequately explored in UC and they are far from being considered as inflammatory cells in this milieu, therefore precise understanding the role of these newly identified cells in particular their potential role in gut pathogenesis may enable us to develop novel therapeutic approaches for inflammatory bowel disease. So, this article tries to discuss the latest knowledge on the above-mentioned field. [ABSTRACT FROM AUTHOR]

The origin of multiple myeloma depends on interactions with stromal cells in the course of normal B-cell differentiation and evolution of immunity. The concept of the present study is that genes involved in MM pathogenesis, such as immune response genes, can be identified by screening for single-nucleotide polymorphisms (SNPs) involved in the immune response and a subsequent statistical analysis that focusses on the association of SNPs, certain haplotypes or SNP–SNP interactions with MM risk and prognosis. We genotyped 348 Danish patients and 355 controls for 13 SNPs located in the TNFA, IL-4, IL-6, IL-10 and CHI3L1 gene promoters. The occurrence of single polymorphisms, haplotypes and SNP–SNP interactions were statistically analyzed for association with disease risk and outcome following high-dose therapy. Identified genes that carried SNPs or haplotypes that were identified as risk or prognostic factors were studied for expression in normal B-cell subsets and myeloma plasma cells. We observed a significantly reduced risk when harboring the TNFA-238A allele (OR = 0.51 (0.29–0.86)) and interactions between the TNFA-1031T/C * and IL-10 -3575T/A (p = .007) as well as the TNFA-308G/A * and IL-10-1082G/A (p = .008) allels. By statistical approaches, we observed association between prognosis and the TNFA-857CC genotype (HR = 2.80 (1.29–6.10)) and IL-10-1082GG + GA genotypes (HR = 1.93 (1.07–3.49)) and interactions between IL-6-174G/C and IL-10-3575T/A (p = .001) and between TNFA-308G/A and IL-4-1098T/G (p= .005). The ‘risk genes’ were analyzed for expression in normal B-cell subsets (N = 6) from seven healthy donors and we found TNFA and IL-6 expressed both in naïve and in memory B cells when compared to preBI, II, immature and plasma cells. The ‘prognosis genes’ CHI3L1, IL-6 and IL-10 were differential expressed in malignant plasma cells when comparing poor and good prognosis groups based on to the TC classification. In summary, these findings suggest that TNFA, IL-4, IL-6, IL-10 and CHI3L1 might be important players in MM pathogenesis during disease initiation and drug resistance in multiple myeloma. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) recently revealed as a potent tumor vaccine component, are commonly differentiated from monocytes by cultivation with IL-4 and GM-CSF. Despite the different opinions, the use of IFNalpha can promote DCs differentiation and activation. The aim of this study was to compare the functionality and phenotypic characterization of monocyte-derived DC generated by IL-4 (IL4DC) and IFNalpha (IFNalphaDC) modified protocols. To this aim, we investigated the expression of maturation markers, co-stimulatory molecules, relevant miRNA, cytokine and migratory profiles and the functional ability of these cells to stimulate autologous T cells in vitro. We herein investigated the molecular mechanism underlying the parameters previously described, as the relative expression of NF-kB p65, c-fos and c-jun, transcription factors. Our results demonstrated that IL4DC presented a stable phenotype, an increase in migratory capacity and NF-KB activation, in addition to lower levels of miR-146 a and miR-221. We believe that the IL4DC migratory potential and increase in NFkBp65 expression may be involved in higher IL12 expression and migration, suggesting a preferential activation of TH1 immune responses by IL4DC. [ABSTRACT FROM AUTHOR]

Conclusions: Our results indicate that chronic rhinosinusitis without nasal polyps (CRSsNP) is characterized by the down-regulation of a Toll-like receptor (TLR)-mediated signaling pathway and such a deficiency within the innate immune system may contribute to the inflammatory process of CRSsNP. In contrast, the inflammatory process found in CRS with nasal polyps (CRSwNP) is characterized by an excessively activated TLR-mediated signaling pathway, which may contribute to the formation of nasal polyps. This study suggests that the pathophysiologic mechanism of CRSsNP and CRSwNP is different. Objective: The nasal mucosa expresses a variety of TLRs that serve in recognizing microorganisms. We investigated the gene expression of a TLR-mediated signaling pathway within two distinctive patient subgroups: CRSwNP and CRSsNP. Methods: Nasal mucosal tissue was obtained from 78 subjects with CRS and 23 control subjects. qRT-PCR and immunohistochemistry were used to investigate tissues for the expression of TLR2, TLR4, TLR7, their downstream signaling components, MyD88 and TRIF, and associated cytokines, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10. Results: TLR2, TLR4, TLR7, and IL-4 were significantly increased in CRSwNP patients when compared with either CRSsNP patients or control subjects, whereas TLR4 and TLR7, and downstream MyD88 were significantly decreased in CRSsNP patients versus patients from CRSwNP and control subjects. [ABSTRACT FROM AUTHOR]

Background. Toll-like receptor (TLR) molecules play critical roles in directing the course of atopic diseases by recognizing specific microbial products that activate immune effector cell function. Objective. We determined if basophils harvested from neonates genetically predisposed to atopic disease had different levels of TLR2 expression and determined whether putative TLR2 ligands mediated cytokine secretion. Methods. Blood samples were collected from 10 asthmatic and 12 healthy women and their newborns. Basophil histamine was measured using the human basophil degranulation test and TLR2 expression was determined using nucleic acid hybridization in situ and flow cytometry. IL-4 levels were quantified by ELISA following allergen stimulation. Results. The basophil degranulation index (DI) in granulocytes harvested from peripheral blood of asthmatic women was assessed following stimulation with either peptidoglycan (PGN) or Dermatophagoides farinae (Df) extract. The DI was significantly higher in atopic women than in healthy controls. Basophils purified from the cord blood of neonates born to atopic mothers produced more IL-4 compared with basophils purified from children born to nonatopic controls. Finally, TLR2 expression at the protein and mRNA levels was upregulated in cord blood basophils from neonates born to mothers with asthma following stimulation with PGN but not Df. Conclusion. These data suggested that TLR2-mediated innate immune responses play a role in augmenting allergic reactions through the modulation of basophil cytokine secretion and histamine release. Microbial components may activate basophils through TLR2 (especially for genetically predisposed infants) to release cytokines associated with an increased incidence of allergic diseases. [ABSTRACT FROM AUTHOR]

Cytokines regulate proliferation, differentiation and activation of osteoblasts. Interleukin-4 (IL-4) and interleukin-13 (IL-13) takes part in this regulation by inhibiting proliferation and by enhancement of interleukin-6 (IL-6) formation in cultured human osteoblasts (hOBs). In the present study we have investigated the effects of IL-4 and IL-13 on markers of osteoblastic activity in isolated hOBs. Treatment with either IL-4 or IL-13 (1–100 pM) stimulated the formation of alkaline phosphatase (ALP) dose-dependently, detected by enzyme reaction and histochemistry. IL-4 and IL-13 also induced an increase in the secretion of procollagen type I carboxypeptide (PICP) from cultured hOBs, measured by RIA. Osteocalcin secretion measured by ELISA-technique was unaffected. The rate of mineralization, assessed by von Kossa and Alizarin Red staining, was clearly enhanced in hOBs stimulated by IL-4 or IL-13. In conclusion IL-4 and IL-13 exert multiple effects on osteoblast activity in cultured hOBs. Stimulation of ALP secretion together with enhanced collagen secretion and mineralization suggests that IL-4 and IL-13 also have the capacity to maintain hOBs in a differentiated, productive phase. [ABSTRACT FROM AUTHOR]

Conclusion. Thymic stromal lymphopoietin (TSLP) played an important role in the pathogenesis of allergic rhinitis (AR) and can be regarded a potential therapeutic target for the management of AR. Objective. To evaluate the possible role of TSLP in the pathogenesis of AR. Patients and methods. We enrolled 16 patients of AR to investigate the expression of TSLP in nasal mucosa and evaluate the link of TSLP and interleukin-4 (IL-4). Expression of TSLP was detected by immunohistochemical analysis and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and concentrations of TSLP and IL-4 were measured by enzyme-linked immunosorbent assay (ELISA). Results. TSLP was detected in all samples and the mRNA and protein expression of TSLP is increased significantly in AR nasal mucosa compared with normal control (P<0.05). TSLP production is tightly correlated with IL-4 and severity of AR (P<0.05). [ABSTRACT FROM AUTHOR]

Crude extracts from traditional herbs have long been used in the treatment of a variety of acute and/or chronic diseases in many countries. Zingiber zerumbet Smith extract has been reported to have anti-inflammatory potential, especially in asthmatic patients. The aim of this study is to examine the capacity of water extract of Zingiber zerumbet (CC-ZWE) in protecting the lungs by inhibiting the release of inflammatory mediators during short-term treatment, and modulating cytokine gene expressions during long-term treatment. BALB/c mice were sensitised and challenged with ovalbumin to induce anaphylaxis. The anti-hypersensitive and anti-inflammatory potentials of water extract of Zingiber zerumbet Smith (ZZ-CWE) were evaluated using both in vitro and in vivo systems. ZZ-CWE decreased the release of tumour necrosis factor-alpha and interleukin-4 (IL-4) in vitro and effectively suppressed LTC4 release from lung tissue in vivo (p<0.05). Additionally, animals treated with ZZ-CWE expressed higher ratios of interferon-gamma/IL-4 mRNA in their splenocytes than that of the control group (p<0.05). Our results showed that ZZ-CWE should have beneficial effects for the treatment of asthmatic patients through its capabilities to inhibit the synthesis of LTC4 and through the immunomodulation of Th1/Th2 cytokine production. [ABSTRACT FROM AUTHOR]

Bronchial epithelial cells play a pivotal role in airway inflammation, but little is known about posttranscriptional regulation of mediator gene expression during the inflammatory response in these cells. Here, we show that activation of human bronchial epithelial BEAS-2B cells by proinflammatory cytokines interleukin-4 (IL-4) and tumor necrosis factor alpha (TNF-α) leads to an increase in the mRNA stability of the key chemokines monocyte chemotactic protein 1 and IL-8, an elevation of the global translation rate, an increase in the levels of several proteins critical for translation, and a reduction of microRNA-mediated translational repression. Moreover, using the BEAS-2B cell system and a mouse model, we found that RNA processing bodies (P bodies), cytoplasmic domains linked to storage and/or degradation of translationally silenced mRNAs, are significantly reduced in activated bronchial epithelial cells, suggesting a physiological role for P bodies in airway inflammation. Our study reveals an orchestrated change among posttranscriptional mechanisms, which help sustain high levels of inflammatory mediator production in bronchial epithelium during the pathogenesis of inflammatory airway diseases. [ABSTRACT FROM AUTHOR]

Serum response factor (SRF) is a crucial transcriptional factor for muscle-specific gene expression. We investigated SRF function in adult skeletal muscles, using mice with a postmitotic myofiber-targeted disruption of the SRF gene. Mutant mice displayed severe skeletal muscle mass reductions due to a postnatal muscle growth defect resulting in highly hypotrophic adult myofibers. SRF-depleted myofibers also failed to regenerate following injury. Muscles lacking SRF had very low levels of muscle creatine kinase and skeletal alpha-actin (SKA) transcripts and displayed other alterations to the gene expression program, indicating an overall immaturity of mutant muscles. This loss of SKA expression, together with a decrease in beta-tropomyosin expression, contributed to myofiber growth defects, as suggested by the extensive sarcomere disorganization found in mutant muscles. However, we observed a downregulation of interleukin 4 (IL-4) and insulin-like growth factor 1 (IGF-1) expression in mutant myofibers which could also account for their defective growth and regeneration. Indeed, our demonstration of SRF binding to interleukin 4 and IGF-1 promoters in vivo suggests a new crucial role for SRF in pathways involved in muscle growth and regeneration. [ABSTRACT FROM AUTHOR]