The chemokine receptor CXCR3 is expressed on malignant B cells and mediates chemotaxis.
(9/1046)
B- and T-cell recirculation is crucial for the function of the immune system, with the control of cell migration being mainly mediated by several chemokines and their receptors. In this study, we investigated the expression and function of CXCR3 on normal and malignant B cells from 65 patients with chronic lymphoproliferative disorders (CLDs). Although CXCR3 is lacking on CD5(+) and CD5(-) B cells from healthy subjects, it is expressed on leukemic B lymphocytes from all (31/31) patients with chronic lymphocytic leukemia (CLL). The presence of CXCR3 was heterogeneous in other B-cell disorders, being expressed in 2 of 7 patients with mantle cell lymphoma (MCL), 4 of 12 patients with hairy cell leukemia (HCL), and 11 of 15 patients with other subtypes of non-Hodgkin's lymphomas (NHLs). Chemotaxis assay shows that normal B cells from healthy subjects do not migrate in response to IFN-inducible protein 10 (IP-10) and IFN-gamma-induced monokine (Mig). In contrast, a definite migration in response to IP-10 and Mig has been observed in all malignant B cells from patients with CLL, but not in patients with HCL or MCL (1/7 cases tested). Neoplastic B cells from other NHLs showed a heterogenous pattern. The migration elicited by IP-10 and Mig was inhibited by blocking CXCR3. No effect of IP-10 and Mig chemokines was observed on the cytosolic calcium concentration in malignant B cells. The data reported here demonstrate that CXCR3 is expressed on malignant B cells from CLDs, particularly in patients with CLL, and represents a fully functional receptor involved in chemotaxis of malignant B lymphocytes. (+info)
Interleukin-18, interferon-gamma, IP-10, and Mig expression in Epstein-Barr virus-induced infectious mononucleosis and posttransplant lymphoproliferative disease.
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T cell immunodeficiency plays an important role in the pathogenesis of posttransplant lymphoproliferative disease (PTLD) by permitting the unbridled expansion of Epstein-Barr virus (EBV)-infected B lymphocytes. However, factors other than T cell function may contribute to PTLD pathogenesis because PTLD infrequently develops even in the context of severe T cell immunodeficiency, and athymic mice that are T-cell-immunodeficient can reject EBV-immortalized cells. Here we report that PTLD tissues express significantly lower levels of IL-18, interferon-gamma (IFN-gamma), Mig, and RANTES compared to lymphoid tissues diagnosed with acute EBV-induced infectious mononucleosis, as assessed by semiquantitative RT-PCR analysis. Other cytokines and chemokines are expressed at similar levels. Immunohistochemistry confirmed that PTLD tissues contain less IL-18 and Mig protein than tissues with infectious mononucleosis. IL-18, primarily a monocyte product, promotes the secretion of IFN-gamma, which stimulates Mig and RANTES expression. Both IL-18 and Mig display antitumor activity in mice involving inhibition of angiogenesis. These results document greater expression of IL-18, IFN-gamma, Mig, and RANTES in lymphoid tissues with acute EBV-induced infectious mononucleosis compared to tissues with PTLD and raise the possibility that these mediators participate in critical host responses to EBV infection. (+info)
During wound healing, fibroblasts are recruited from the surrounding tissue to accomplish repair. The requisite migration and proliferation of the fibroblasts is promoted by growth factors including those that activate the epidermal growth factor receptor (EGFR). Counterstimulatory factors in wound fluid are postulated to limit this response; among these factors is the ELR-negative CXC chemokine, interferon inducible protein-10 (IP-10). We report here that IP-10 inhibited EGF- and heparin-binding EGF-like growth factor-induced Hs68 human dermal fibroblast motility in a dose-dependent manner (to 52% and 44%, respectively, at 50 ng/ml IP-10), whereas IP-10 had no effect on either basal or EGFR-mediated mitogenesis (96 +/- 15% at 50 ng/ml). These data demonstrate for the first time a counterstimulatory effect of IP-10 on a specific induced fibroblast response, EGFR-mediated motility. To define the molecular basis of this negative transmodulation of EGFR signaling, we found that IP-10 did not adversely impact receptor or immediate postreceptor signaling as determined by tyrosyl phosphorylation of EGFR and two major downstream effectors phospholipase C-gamma and erk mitogen-activated protein kinases. Morphological studies suggested which biophysical steps may be affected by demonstrating that IP-10 treatment resulted in an elongated cell morphology reminiscent of failure to detach the uropod; in support of this, IP-10 pretreatment inhibited EGF-induced cell detachment. These data suggested that calpain activity may be involved. The cell permeant agent, calpain inhibitor I, limited EGF-induced motility and de-adhesion similarly to IP-10. IP-10 also prevented EGF- induced calpain activation (reduced by 71 +/- 7%). That this inhibition of EGF-induced calpain activity was secondary to IP-10 initiating a cAMP-protein kinase A-calpain cascade is supported by the following evidence: (a) the cell permeant analogue 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) prevented EGF-induced calpain activity and motility; (b) other ELR-negative CXC chemokines, monokine induced by IFN-gamma and platelet factor 4 that also generate cAMP, inhibited EGF-induced cell migration and calpain activation; and (c) the protein kinase A inhibitor Rp-8-Br-cAMPS abrogated IP-10 inhibition of cell migration, cell detachment, and calpain activation. Our findings provide a model by which IP-10 suppresses EGF-induced cell motility by inhibiting EGF-induced detachment of the trailing edges of motile cells. (+info)
Interferon-gamma (IFN-gamma)-dependent protection and synthesis of chemoattractants for mononuclear leucocytes caused by IL-12 in the lungs of mice infected with Cryptococcus neoformans.
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We have recently demonstrated that IL-12 induced cellular inflammatory responses consisting mainly of accumulation of mononuclear leucocytes in the lungs of mice infected with Cryptococcus neoformans and protected mice against fulminant infection. We examined the involvement of endogenously synthesized IFN-gamma in such a response by investigating the effects of a neutralizing monoclonal antibody against this cytokine. The latter treatment completely abrogated the positive effects of IL-12 on survival of infected mice and prevented IL-12-induced elimination of microbials from the lungs. Histopathological examination showed that accumulation of mononuclear leucocytes in the infected lungs caused by IL-12 was clearly inhibited by anti-IFN-gamma MoAb. We also examined the local production of mononuclear cell-attracting chemokines such as monocyte chemotactic protein-1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta and IFN-gamma-inducible protein 10 (IP-10) in the lungs using a reverse transcriptase-polymerase chain reaction (RT-PCR) method. We found that these chemokines were not synthesized in the infected lungs, while IL-12 treatment markedly induced their production. Interestingly, neutralizing anti-IFN-gamma MoAb strongly suppressed IL-12-induced production of these chemokines. Similar results were obtained with MCP-1 and MIP-1alpha when their synthesis was measured at the protein level using respective ELISA kits. Our results indicate that IFN-gamma plays a central role in the protective effects of IL-12 by inducing mononuclear leucocyte-attracting chemokines and cellular inflammatory responses. (+info)
Cholecystokinin induction of mob-1 chemokine expression in pancreatic acinar cells requires NF-kappaB activation.
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Inflammatory mediators are involved in the early phase of acute pancreatitis, but the cellular mechanisms responsible for their generation within pancreatic cells are unknown. We examined the role of nuclear factor-kappaB (NF-kappaB) in cholecystokinin octapeptide (CCK-8)-induced mob-1 chemokine expression in pancreatic acinar cells in vitro. Supraphysiological, but not physiological, concentrations of CCK-8 increased inhibitory kappaB (IkappaB-alpha) degradation, NF-kappaB activation, and mob-1 gene expression in isolated pancreatic acinar cells. CCK-8-induced IkappaB-alpha degradation was maximal within 1 h. Expression of mob-1 was maximal within 2 h. Neither bombesin nor carbachol significantly increased mob-1 mRNA or induced IkappaB-alpha degradation. Thus the concentration, time, and secretagogue dependence of mob-1 gene expression and IkappaB-alpha degradation were similar. Inhibition of NF-kappaB with pharmacological agents or by adenovirus-mediated expression of the inhibitory protein IkappaB-alpha also inhibited mob-1 gene expression. These data indicate that the NF-kappaB signaling pathway is required for CCK-8-mediated induction of mob-1 chemokine expression in pancreatic acinar cells. This supports the hypothesis that NF-kappaB signaling is of central importance in the initiation of acute pancreatitis. (+info)
Elevated chemokine concentrations in sera of human immunodeficiency virus (HIV)-seropositive and HIV-seronegative patients with tuberculosis: a possible role for mycobacterial lipoarabinomannan.
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Levels of interleukin 8 (IL-8), gamma interferon-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1beta (MIP-1beta) were elevated in patients with tuberculosis. IP-10 and MCP-1 levels were higher in human immunodeficiency virus (HIV)-seropositive patients than in HIV-seronegative patients with tuberculosis. Lipoarabinomannan induced IL-8, MCP-1, and MIP-1beta in vitro, which was partly inhibited by anti-tumor necrosis factor antibody. (+info)
Increased expression of IP-10, IL-8, MCP-1, and MCP-3 in ulcerative colitis.
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Chemokines are thought to be important for the recruitment of granulocytes and mononuclear cells and thus for the maintenance of inflammation in ulcerative colitis (UC). We have studied the expression of interferon-gamma inducible protein-10 (IP-10), interleukin-8 (IL-8), monocyte chemoattractant protein (MCP)-1, MCP-3, and macrophage inflammatory protein (MIP)-1alpha in UC patients and control individuals to assess the role of these chemokines in disease progression. Colonic biopsies were taken endoscopically from patients and controls, frozen immediately and subsequently stained for IP-10, IL-8, MCP-1, MCP-3, and MIP-1alpha in serial sections. Cells infiltrating the lamina propria but not epithelial cells express the analyzed chemokines. They were differentiated and counted, and chemokine-expressing cells were quantified by image analysis. The percentage of cells expressing IP-10, IL-8, MCP-1, and MCP-3 was significantly enhanced in all UC samples as compared to controls. Expression in the controls was borderline, except for IP-10. No expression of MIP-1alpha was found in controls and UC. IP-10 was also markedly expressed in the mucosa of control biopsies and therefore could have a role in activated T lymphocytes' recruitment into the healthy mucosa. (+info)
SLC/exodus2/6Ckine/TCA4 induces chemotaxis of hematopoietic progenitor cells: differential activity of ligands of CCR7, CXCR3, or CXCR4 in chemotaxis vs. suppression of progenitor proliferation.
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Chemokines induce chemotaxis of hematopoietic progenitor cells (HPC), and suppress their proliferation. In this study we report that SLC/ Exodus2/6Ckine/TCA4 (hereafter termed SLC) is a chemoattractant for human CD34+ HPC. SLC mainly induces preferential chemotaxis of macrophage progenitors. We examined the chemotactic activity of CXCR3 ligands on CD34+ HPC because it has been reported that SLC is a potential ligand of CXC chemokine receptor, CXCR3, in addition to a CC chemokine receptor, CCR7. It was found that the CXCR3 ligands, MIG and interferon-gamma inducible protein-10 (IP-10), unlike SLC, did not induce chemotaxis of CD34+ HPC. In this regard, CCR7 ligands (SLC and CKbeta-11), but not IP-10 and MIG, induce actin polymerization in CD34+ cells. On the other hand, CCR7 ligands and CXCR3 ligands, but not the CXCR4 ligand SDF-1, showed inhibitory activity for proliferation of myeloid progenitor cells. Our results suggest that SLC is a potential trafficking factor for HPC, and that chemokines that bind CCR7, CXCR4, and CXCR3 have differential biological activities on HPC in terms of suppression and chemotaxis. (+info)