PPAR-gamma activation inhibits angiogenesis by blocking ELR+CXC chemokine production in non-small cell lung cancer. (57/169)

Activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) results in inhibition of tumor growth in various types of cancers, but the mechanism(s) by which PPAR-gamma induces growth arrest has not been completely defined. In a recent study, we demonstrate that treatment of A549 (human non small cell lung cancer cell line) tumor-bearing SCID mice with PPAR-gamma ligands troglitazone (Tro) and pioglitazone significantly inhibits primary tumor growth. In this study, immunohistochemical analysis of Tro-treated and Pio-treated tumors with factor VIII antibody revealed a significant reduction in blood vessel density compared to tumors in control animals, suggesting inhibition of angiogenesis. Further analysis showed that treatment of A549 cells in vitro with Tro or transient transfection of A549 cells with constitutively active PPAR-gamma (VP16-PPAR-gamma) construct blocked the production of the angiogenic ELR+CXC chemokines IL-8 (CXCL8), ENA-78 (CXCL5), and Gro-alpha (CXCL1). Similarly, an inhibitor of NF-kappa B activation (PDTC) also blocked CXCL8, CXCL5, and CXCL1 production, consistent with their NF-kappa B-dependent regulation. Conditioned media from A549 cells induce human microvascular endothelial cell (HMVEC) chemotaxis. However, conditioned media from Tro-treated A549 cells induced significantly less HMVEC chemotaxis compared to untreated A549 cells. Furthermore, PPAR-gamma activation inhibited NF-kappa B transcriptional activity, as assessed by TransAM reporter gene assay. Collectively, our data suggest that PPAR-gamma ligands can inhibit tumor-associated angiogenesis by blocking the production of ELR+CXC chemokines, which is mediated through antagonizing NF-kappaB activation. These antiangiogenic effects likely contribute to the inhibition of primary tumor growth by PPAR-gamma ligands.  (+info)

Roles for CXC chemokine ligands 10 and 11 in recruiting CD4+ T cells to HIV-1-infected monocyte-derived macrophages, dendritic cells, and lymph nodes. (58/169)

We investigated roles for chemoattractants in dissemination of HIV-1 by examining the induction of T cell-active chemokines in HIV-1-infected human monocyte-derived macrophages and dendritic cells. Of the 12 chemokines analyzed, mRNAs for two, CXCL10 and CXCL11, ligands for the chemokine receptor CXCR3, were up-regulated in both cell types upon infection by HIV-1. Induction of these chemokine genes in infected cultures was dependent on both viral entry and reverse transcriptase activity, but not on the HIV-1 envelope glycoprotein. Conditioned medium from infected cells was chemotactic for freshly isolated human CD4+ T cells, and chemotaxis was abolished by pretreatment with an Ab against CXCR3. A lymph node from an HIV-1-infected individual expressed CXCL10 and CXCL11 mRNAs in the paracortex, including venules, as detected by in situ hybridization, whereas neither mRNA was detected after highly active antiretroviral therapy. Because CCR5 on CD4+ T cells is found predominantly on cells that also express CXCR3, these data implicate CXCL10 and CXCL11 in the recruitment of susceptible T cells to HIV-1-infected lymph nodes, macrophages, and dendritic cells. This recruitment might enhance the sequestration of T cells in infected lymphoid organs and the spread of infection between cells, contributing to the immunopathology of AIDS.  (+info)

Synthesis of alpha-chemokines IP-10, I-TAC, and MIG are differentially regulated in human corneal keratocytes. (59/169)

PURPOSE: Chemokines responsible for recruiting lymphocytes such as activated T cells into the cornea have not been clearly defined. IP-10, I-TAC, and MIG are chemoattractants for these lymphocytes. The goal of this study was to determine whether human corneal keratocyte (HCKs) in culture synthesize these chemokines in response to proinflammatory mediators. METHODS: HCKs grown in vitro were stimulated with IL-1alpha, TNF-alpha, or IFN-gamma. Induction of alpha-chemokine gene expression was quantitated by real-time PCR and ELISA. Activation of the transcriptional activator STAT1 by IFN-gamma receptors expressed on HCKs was determined by Western blot analysis. RESULTS: HCKs incubated with TNF-alpha, IL-1alpha, or IFN-gamma resulted in a >2000-fold increase in IP-10 protein secretion by 36 hours after stimulation. In contrast, stimulation with TNF-alpha, IL-1alpha, or IFN-gamma induced levels of MIG and I-TAC that were not significantly greater than constitutive levels. Treatment of HCKs with IFN-gamma activated STAT1 and, in combination with either TNF-alpha or IL-1alpha, enhanced MIG and I-TAC synthesis >20-fold. CONCLUSIONS: IP-10 synthesis is induced in HCKs by IL-1alpha, TNF-alpha, and IFN-gamma. In contrast, induction of I-TAC and MIG synthesis in HCKs requires costimulation with IFN-gamma and either IL-1alpha or TNF-alpha. The results suggest therefore, that the upregulation of I-TAC and MIG gene expression at sites of corneal inflammation are more tightly regulated than that of IP-10. A role for differential induction of the three alpha-chemokine genes in corneal inflammatory processes at the eye surface is discussed.  (+info)

Plasma chemokine levels correlate with the outcome of antiviral therapy in patients with hepatitis C. (60/169)

Chronic infection with the hepatitis C virus (HCV) is associated with failures of T-cell-mediated immune clearance and with abnormal B-cell growth and activation. We examined the levels of chemokines that bind to CXC chemokine receptor 3 (CXCR3) to determine whether such chemokines might play a role in the failure of the immune system to clear HCV infection. Elevations in CXC ligand 9 (CXCL9), CXCL10, and CXCL11 were observed in all patients with HCV. CXCR3 expression was increased significantly on peripheral blood B lymphocytes, but not T lymphocytes, from individuals with HCV infection. Chemokine levels were measured in samples collected before, during, and after antiviral therapy from a group of 29 patients infected with HCV genotypes 1a (24 patients) and 1b (5 patients). Levels of CXCL10 and CXCL9 decreased following successful antiviral therapy; CXCL11 did not decline significantly during or in the first 6 months after therapy. The baseline level of CXCL10 (measured before the start of antiviral treatment) was greatest in patients with HCV who subsequently became nonresponders to therapy. These results suggest that plasma concentrations of immunoreactive CXCL10 may be a predictor of responsiveness or nonresponsiveness to antiviral therapy with pegylated interferon (IFN) with or without ribavirin. This observation has implications for understanding the pathogenesis of HCV infection.  (+info)

Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: An amplification cycle triggering cutaneous lupus erythematosus. (61/169)

OBJECTIVE: To investigate the activation and recruitment pathways of relevant leukocyte subsets during the initiation and amplification of cutaneous lupus erythematosus (LE). METHODS: Quantitative real-time polymerase chain reaction was used to perform a comprehensive analysis of all known chemokines and their receptors in cutaneous LE lesions, and the cellular origin of these chemokines and receptors was determined using immunohistochemistry. Furthermore, cytokine- and ultraviolet (UV) light-mediated activation pathways of relevant chemokines were investigated in vitro and in vivo. RESULTS: In the present study, we identified the CXCR3 ligands CXCL9 (interferon-gamma [IFNgamma]-induced monokine), CXCL10 (IFNgamma-inducible protein 10), and CXCL11 (IFN-inducible T cell alpha chemoattractant) as being the most abundantly expressed chemokine family members in cutaneous LE. Expression of these ligands corresponded with the presence of a marked inflammatory infiltrate consisting of mainly CXCR3-expressing cells, including skin-homing lymphocytes and blood dendritic cell antigen 2-positive plasmacytoid dendritic cells (PDCs). Within cutaneous LE lesions, PDCs accumulated within the dermis and were activated to produce type I IFN, as detected by the expression of the IFNalpha-inducible genes IRF7 and MxA. IFNalpha, in turn, was a potent and rapid inducer of CXCR3 ligands in cellular constituents of the skin. Furthermore, we demonstrated that the inflammatory CXCR3 ligands cooperate with the homeostatic chemokine CXCL12 (stromal cell-derived factor 1) during the recruitment of pathogenically relevant leukocyte subsets. Moreover, we showed that UVB irradiation induces the release of CCL27 (cutaneous T cell-attracting chemokine) from epidermal compartments into dermal compartments and up-regulates the expression of a distinct set of chemokines in keratinocytes. CONCLUSION: Taken together, our data suggest an amplification cycle in which UV light-induced injury induces apoptosis, necrosis, and chemokine production. These mechanisms, in turn, mediate the recruitment and activation of autoimmune T cells and IFNalpha-producing PDCs, which subsequently release more effector cytokines, thus amplifying chemokine production and leukocyte recruitment, finally leading to the development of a cutaneous LE phenotype.  (+info)

Recruitment of CXCR3+ and CCR5+ T cells and production of interferon-gamma-inducible chemokines in rejecting human arteries. (62/169)

Chemokine receptors preferentially expressed by Th1 cells and their IFN-gamma-inducible ligands predominate in experimental and clinical allograft rejection. Previous chemokine-related transplantation studies have focused on parenchymal and microvascular inflammation which are of importance in acute rejection, but are not necessarily relevant in immune-mediated injury of conduit arteries. We have recently described a model of progressive human T cell-mediated infiltration and injury of allogeneic coronary artery segments using immunodeficient mouse hosts. In the present study, we investigated if recruitment of allogeneic T cells to different vascular compartments correlated with the expression of chemokines and their receptors. Transcripts were quantified by laser capture microdissection/real-time RT-PCR and their distribution was correlated to the corresponding protein expression detected by immunohistochemistry. Infiltrating T cells, confined to the adventitia and intima, expressed CXCR3 and CCR5, but were not recruited into the media despite production by vascular smooth muscle cells of IP-10, Mig, I-TAC, RANTES and MIP-1beta. Chemokine mRNA was detected primarily in vascular cells, although chemokine protein largely localized to infiltrating leukocytes which uniquely expressed their cognate receptors. These data explain the recruitment of IFN-gamma-secreting T cells to the vessel wall, and reinforce the suggestion that the arterial media may be a site of immunological privilege.  (+info)

Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. (63/169)

Thymic stromal lymphopoietin (TSLP) is said to increase expression of chemokines attracting Th2 T cells. We hypothesized that asthma is characterized by elevated bronchial mucosal expression of TSLP and Th2-attracting, but not Th1-attracting, chemokines as compared with controls, with selective accumulation of cells bearing receptors for these chemokines. We used in situ hybridization and immunohistochemistry to examine the expression and cellular provenance of TSLP, Th2-attracting (thymus and activation-regulated chemokine (TARC)/CCL17, macrophage-derived chemokine (MDC)/CCL22, I-309/CCL1) and Th1-attracting (IFN-gamma-inducible protein 10 (IP-10)/CXCL10, IFN-inducible T cell alpha-chemoattractant (I-TAC)/CXCL11) chemokines and expression of their receptors CCR4, CCR8, and CXCR3 in bronchial biopsies from 20 asthmatics and 15 normal controls. The numbers of cells within the bronchial epithelium and submucosa expressing mRNA for TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in asthmatics as compared with controls (p +info)

Identification of novel genes in intestinal tissue that are regulated after infection with an intestinal nematode parasite. (64/169)

Infection of resistant or susceptible mice with Trichuris muris provokes mesenteric lymph node responses which are polarized towards Th2 or Th1, respectively. These responses are well documented in the literature. In contrast, little is known about the local responses occurring within the infected intestine. Through microarray analyses, we demonstrate that the gene expression profile of infected gut tissue differs according to whether the parasite is expelled or not. Genes differentially regulated postinfection in resistant BALB/c mice include several antimicrobial genes, in particular, intelectin (Itln). In contrast, analyses in AKR mice which ultimately progress to chronic infection provide evidence for a Th1-dominated mucosa with up-regulated expression of genes regulated by gamma interferon. Increases in the expression of genes associated with tryptophan metabolism were also apparent with the coinduction of tryptophanyl tRNA synthetase (Wars) and indoleamine-2,3-dioxygenase (Indo). With the emerging literature on the role of these gene products in the suppression of T-cell responses in vitro and in vivo, their up-regulated expression here may suggest a role for tryptophan metabolism in the parasite survival strategy.  (+info)