Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously we have shown that adenovirus-mediated gene transfer and expression of vIL-10 are able to prolong cardiac allograft survival, through the inhibition of the immune response to both alloantigen and adenoviral antigens. In the current study, we have defined further mechanisms of Ad.vIL-10-mediated prolongation of cardiac allograft survival. E1- and E3-deleted adenoviral vectors encoding beta-galactosidase or vIL-10 were transferred into grafts at the time of transplantation, chemokine and chemokine receptor expression were evaluated by a pathway-specific cDNA array, and the results were confirmed with real time RT-PCR on selected genes. Ischemic injury, alloantigen and adenovirus vector induced the expression of multiple pro-inflammatory chemokines in the grafts, which likely amplify allograft rejection. Most of these Th1-related chemokine genes were inhibited or down-regulated by Ad.vIL-10 administration, which may help to decrease leukocytic infiltration and improve graft survival. Among the potent Th1 type chemokines inhibited were the CXCR3 ligands CXCL9 and CXCL10, which could directly inhibit vector-mediated gene expression in myoblasts, although targeting CXCR3 or its ligands did not prolong allograft survival with vIL-10 gene transfer. Ad.vIL-10 administration also induced the expression of the Th2-associated chemokines eotaxin-2 and MIP-1 gamma, suggesting Th1 to Th2 immune deviation. These results demonstrated that the vIL-10 gene transfer inhibits chemokine expression, preventing stimulation of innate and adaptive immunity.
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PMID:Viral IL-10 gene transfer inhibits the expression of multiple chemokine and chemokine receptor genes induced by inflammatory or adaptive immune stimuli. 1462 84

Influenza A virus replicates in the respiratory epithelium and induces an inflammatory infiltrate comprised of mononuclear cells and neutrophils. To understand the development of the cell-mediated immune response to influenza and how leukocyte trafficking to sites of inflammation is regulated, we examined the chemokine expression pattern in lung tissue from A/PR/8/34-infected C57BL/6 mice using an RNase protection assay. Monocyte chemoattractant protein 1, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, MIP-3alpha, regulated on activation, normal T expressed and secreted (RANTES), MIP-2, and interferon-inducible protein 10 (IP-10) mRNA expression was up-regulated between days 5 and 15 after infection, consistent with a role for these chemokines in leukocyte recruitment to the lung. Low levels of expression were detected for the CC chemokine receptors (CCR)2 and CCR5, whereas CXC chemokine receptor (CXCR)3 was significantly up-regulated by day 10 after infection, coinciding with peak inflammatory cell infiltration in the airways. As RANTES, IP-10, and their receptors were up-regulated during influenza virus infection, we investigated leukocyte recruitment and viral clearance in mice deficient in RANTES or CXCR3, the receptor for IP-10. Leukocyte recruitment and viral replication in influenza-infected RANTES knockout(-/-) mice were similar to that in control mice, showing that RANTES is not essential for the immune response to influenza infection. Similarly, leukocyte recruitment and viral replication in CXCR3-/- mice were identical to control mice, except at day 8 postinfection, where fewer lymphocytes, neutrophils, and eosinophils were detected in the bronchoalveolar lavage of CXCR3-/- mice. These studies suggest that although the chemokines detected may play a role in regulating leukocyte trafficking to the lung during influenza infection, some may be functionally redundant.
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PMID:Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice. 1524 Jul 57

Intranasal inoculation of mice with Bordetella bronchiseptica produces a transient pneumonia that is cleared over several weeks in a process known to require both neutrophils and lymphocytes. In this study, we evaluated the roles of the chemokines MIG (CXCL9), IP-10 (CXCL10), and I-TAC (CXCL11) and their common receptor, CXCR3. Following bacterial inoculation, message expression of interleukin-1 (IL-1), IL-6, and the neutrophil-attracting chemokines KC, LIX, and MIP-2 was rapidly induced, with maximal expression found at 6 h. In contrast, message expression of gamma interferon, MIG, IP-10, and I-TAC peaked at 2 days. Expression of all of these chemokines and cytokines returned to near baseline by 5 days, despite the persistence of high levels of live bacteria at this time. Induced MIG, IP-10, and I-TAC protein expression was localized in areas of inflammation at 2 to 3 days and was temporally associated with increased levels of CXCR3(+) lymphocytes in bronchoalveolar lavage fluid. There was no increase in mortality in mice lacking CXCR3. However, the clearance of bacteria from the lung and trachea was delayed, and the recruitment of lymphocytes and NK cells was slightly decreased, for CXCR3(-/-) mice relative to CXCR3(+/+) mice. We conclude that the CXCR3 receptor-ligand system contributes to pulmonary host defense in B. bronchiseptica infection by recruiting lymphocytes and NK cells into the lung.
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PMID:CXCR3 and its ligands participate in the host response to Bordetella bronchiseptica infection of the mouse respiratory tract but are not required for clearance of bacteria from the lung. 1561 88

Infiltration by mononuclear cells is found within the renal tissue in various types of kidney diseases. The migration of leukocytes through vessels and beyond the vascular compartment is dependent in part on small chemoattractant proteins called chemokines. All types of renal cells can produce chemokines in a cell- and stimulus-specific manner. Some chemokines appear to be constitutively expressed, while proinflammatory chemokines are expressed only in responses to specific stimuli. MCP-1 expression in renal tubuli is enhanced in proteinuric states, irrespective of the types of renal disease, and this increased MCP-1 expression probably contributes to renal tubular damage in proteinuric states. Expression of individual chemokines correlate with intrarenal T cells and monocyte/macrophage infiltrates as well as with interstitial kidney damage and renal function. Experimental data and studies on human renal tissue in patients with glomerulonephritis and renal allograft rejection indicate that MCP-1, MIP-lalpha, beta, RANTES, and IL-8 play a main role in the resolution and progression of inflammatory processes in these cases. Renal cells and inflammatory cells also express chemokine receptors, especially CCR-5, CCR-1, CCR-2, and CXCR3. Analysis of the immunoexpression of chemokines and chemokine receptors in renal tissue of patients with glomerulonephritis and renal allograft rejection may be helpful in evaluating the progression of kidney disease, whereas monitoring chemokines in the urine may provide a dynamic picture of the inflammatory state. The pharmacological regulation of chemokine and chemokine receptor expression may be a useful tool in the therapy of kidney diseases.
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PMID:Chemokines and chemokine receptors in glomerulonephritis and renal allograft rejection. 1726 94

Histamine (HA), a biogenic amine with a broad spectrum of activities in both physiological and pathological settings, plays a key regulatory role in experimental allergic encephalomyelitis, the autoimmune model of multiple sclerosis. HA exerts its effect through four G protein-coupled receptors designated HA receptor H1, H2, H3, and H4. We report here that, compared with wild-type animals, mice with a disrupted HA H3 receptor (H3RKO), the expression of which is normally confined to cells of the nervous system, develop more severe disease and neuroinflammation. We show that this effect is associated with dysregulation of blood-brain barrier permeability and increased expression of MIP-2, IP-10, and CXCR3 by peripheral T cells. Our data suggest that pharmacological targeting of the H3R may be useful in preventing the development and formation of new lesions in multiple sclerosis, thereby significantly limiting the progression of the disease.
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PMID:Central histamine H3 receptor signaling negatively regulates susceptibility to autoimmune inflammatory disease of the CNS. 1754 17

Tissue trauma in the peritoneal and pelvic cavities following surgery or bacterial infection results in adhesions that are a debilitating cause of intestinal obstruction, chronic pelvic pain, and infertility in women. We recently demonstrated that CD4(+) alphabeta T cells are essential for development of this process. Using a murine model of experimental adhesion formation, we now demonstrate that adhesion formation is characterized by the selective recruitment of Tim-3(+), CCR5(+), CXCR3(+), IFN-gamma(+) cells, indicating the presence of a Th1 phenotype. We further demonstrate that adhesion formation is critically dependent on the function of Th1 cells because mice genetically deficient for IFN-gamma, T-bet, or treated with Abs to the Th1-selective chemoattractant IL-16 show significantly less adhesion formation than wild-type mice. In addition, disrupting the interaction of the Th1-specific regulatory molecule Tim-3, with its ligand, significantly exacerbates adhesion formation. This enhanced response is associated with increases in the level of neutrophil-attracting chemokines KC and MIP-2, known to play a role in adhesiogenesis. These data demonstrate that the CD4(+) T cells orchestrating adhesion formation are of the Th1 phenotype and delineate the central role of T-bet, Tim-3, IFN-gamma, and IL-16 in mediating this pathogenic tissue response.
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PMID:Functional Th1 cells are required for surgical adhesion formation in a murine model. 1845 19

Chemokines produced in the liver during hepatitis C virus (HCV) infection induce migration of activated T cells from the periphery to infected parenchyma. The milieu of chemokines secreted by infected hepatocytes is predominantly associated with the T-helper cell/Tc1 T cell (Th1/Tc1) response. These chemokines consist of CCL3 (macrophage inflammatory protein-1 alpha; MIP-1 alpha), CCL4 (MIP-1 beta), CCL5 (regulated on activation normal T cell expressed and secreted; RANTES), CXCL10 (interferon-gamma-inducible protein-10; IP-10), CXCL11 (interferon-inducible T-cell alpha chemoattractant; I-TAC), and CXCL9 (monokine induced by interferon gamma; Mig) and they recruit T cells expressing either CCR5 or CXCR3 chemokine receptors. Intrahepatic and peripheral blood levels of these chemokines are increased during chronic hepatitis C. The interaction between chemokines and their receptors is essential in recruiting HCV-specific T cells to control the infection. When the adaptive immune response fails in this task, non-specific T cells without the capacity to control the infection are also recruited to the liver, and these are ultimately responsible for the persistent hepatic damage. The modulation of chemokine receptor expression and chemokine secretion could be a viral escape mechanism to avoid specific T cell migration to the liver during the early phase of infection, and to maintain liver viability during the chronic phase, by impairing non-specific T cell migration. Some chemokines and their receptors correlate with liver damage, and CXCL10 (IP-10) and CXCR3 levels have shown a clinical utility as predictors of treatment response outcome. The regulation of chemokines and their receptors could be a future potential therapeutic target to decrease liver inflammation and to increase specific T cell migration to the infected liver.
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PMID:Role of chemokines and their receptors in viral persistence and liver damage during chronic hepatitis C virus infection. 1908 27

MIP-2 and IFN-gamma inducible protein-10 (IP-10) and their respective receptors, CXCR2 and CXCR3, modulate tissue inflammation by recruiting neutrophils or T cells from the spleen or bone marrow. Yet, how these chemokines modulate diseases such as immune-mediated drug-induced liver injury (DILI) is essentially unknown. To investigate how chemokines modulate experimental DILI in our model we used susceptible BALB/c (WT) and IL-4-/- (KO) mice that develop significantly reduced hepatitis and splenic T cell priming to anesthetic haptens and self proteins following TFA-S100 immunizations. We detected CXCR2+ splenic granulocytes in all mice two weeks following immunizations; by three weeks, MIP-2 levels (p<0.001) and GR1+ cells were elevated in WT livers, suggesting MIP-2-recruited granulocytes. Elevated splenic CXCR3+CD4+T cells were identified after two weeks in KO mice indicating elevated IP-10 levels which were confirmed during T cell priming. This result suggested that IP-10 reduced T cell priming to critical DILI antigens. Increased T cell proliferation following co-culture of TFA-S100-primed WT splenocytes with anti-IP-10 (p<0.05) confirmed that IP-10 reduced T cell priming to CYP2E1 and TFA. We propose that MIP-2 promotes and IP-10 protects against the development of hepatitis and T cell priming in this murine model.
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PMID:IP-10 protects while MIP-2 promotes experimental anesthetic hapten - induced hepatitis. 1913 Dec 11

CD4(+) Th1 cells play a critical role in orchestrating host defense against pathogens and in the pathogenesis of many immune-mediated diseases. The control of Th1 cell trafficking into sites of infection and inflammation is an important determinant of Th1 cell function. We have previously shown that trafficking of adoptively transferred Ag-specific Th1 cells into the lung following airway Ag challenge depends on CXCR3 expression on Th1 cells and STAT1-inducible CXCR3 ligands in the lung. In this study, we show that LPS alters the mechanisms of Th1 cell recruitment. After a single intranasal dose of LPS, trafficking of adoptively transferred Ag-specific Th1 cell into the lung in response to airway Ag challenges was no longer dependent on CXCR3 and its ligands and instead was mediated through additional Galphai-coupled chemoattractant receptor pathways, including CCR5. In addition, LPS markedly increased the magnitude of Ag-specific Th1 cell homing into the airways following airway Ag challenges. The increased trafficking of Ag-activated Th1 cells, in turn, dramatically amplified LPS-induced airway neutrophilic infiltration by maintaining high levels of the neutrophil active chemokines, KC and MIP-2, through an IFN-gamma dependent mechanism. Therefore, LPS increases Ag-specific Th1 cell trafficking into the airways and Ag-specific Th1 cells amplify the airway neutrophilic inflammatory response initiated by LPS. This reciprocal interaction between LPS and Ag-activated Th1 cells represents a collaborative connection between the innate and adaptive arms of the immune system.
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PMID:Endotoxin augmented antigen-induced Th1 cell trafficking amplifies airway neutrophilic inflammation. 1949 19

Chemokines play a critical role in the acute transplant rejection. In order to provide an overview of the chemokine expression during the course of acute allograft rejection, the intragraft expression profile of 11 chemokines representative of all four chemokine subfamilies was analyzed in a murine skin transplantation model of acute rejection. It was found that RANTES/CCL5, TARC/CCL17 and FKN/CX(3)CL1 were expressed at equivalent levels in iso- and allografts. However, the other eight chemokines expression was up-regulated to some extent in allograft compared with that in isograft. The levels of MIP-1alpha/CCL3, MIP-3alpha/CCL20 and CTACK/CCL27 were progressively increased from early stage (day 3 post-transplantation) to late stage (day 11). Mig/CXCL9, IP-10/CXCL10, I-TAC/CXCL11, CXCL16 and LTN/XCL1 expression was elevated at middle stage (day 7), and peaked at late stage. Among the up-regulated chemokines, I-TAC was the most obviously elevated chemokine. Therefore, the effect of I-TAC on the skin acute allograft rejection was evaluated. Block of I-TAC by the intradermal injection of anti-I-TAC monoclonal antibody (mAb) reduced the number of CXCR3(+) cells in skin allograft and significantly prolonged the skin allograft survival. The mAb treatment did not influence the proliferation of the intragraft infiltrating cells in response to the allogeneic antigens, but significantly decreased the number of the infiltrating cells and consequently lowered the secretion of IFN-gamma and TNF-alpha. These data indicate I-TAC might be a dominant chemokine involved in the intradermal infiltration and I-TAC-targeted intervening strategies would have potential application for the alleviation of acute transplant rejection.
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PMID:I-TAC is a dominant chemokine in controlling skin intragraft inflammation via recruiting CXCR3+ cells into the graft. 1987 6


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