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

Gamma interferon (IFN-gamma) has been proposed to play an important role in Helicobacter-related gastritis. Using the IFN-gamma gene knockout (IFN-gamma(-/-)) mouse model and a murine gastric epithelial cell line, GSM06, we demonstrated that Helicobacter pylori maximally induced macrophage inflammatory protein-2 (MIP-2) and inducible nitric oxide synthase (iNOS) mRNA only in wild-type mice. MIP-2 and iNOS mRNA were also induced by H. pylori in GSM06 cells. Induction of cyclooxygenase 2 mRNA through IFN-gamma was demonstrated in GSM06 cells. These data indicate that IFN-gamma mediates the induction of MIP-2 and iNOS mRNA expression by H. pylori in mice.
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PMID:Role of gamma interferon in Helicobacter pylori induction of inflammatory mediators during murine infection. 1201 Oct 29

IL-15 and IL-12 display anti-tumor activity in different models and IFN-gamma has been reported as a secondary mediator of both IL-12 and IL-15 effects. TS/A murine adenocarcinoma cells were engineered to secrete IL-12, IL-15 or both cytokines. TS/A cells secreting IL-15 (TS/A-IL-15) displayed a reduced tumorigenicity (50%) when implanted subcutaneously in syngeneic mice, while both TS/A-IL-12 and TS/A-IL-12/IL-15 were rejected by 100% of animals. In contrast, TS/A-IL-15 and TS/A-IL-12 were tumorigenic in syngeneic IFN-gamma knockout mice (100% and >90% of take rate, respectively), but TS/A-IL-12/IL-15 were completely rejected by 90% of these mice. All IFN-gamma-deficient mice rejecting TS/A-IL-12/IL-15 developed protective immunity against wild-type TS/A, as indicated by re-challenge experiments. Immunohistochemical analysis of the TS/A-IL-12/IL-15 tumor rejection area in IFN-gamma-deficient mice showed a marked reactive cell infiltration constituted of CD8+ cells, granulocytes, NK cells, macrophages and dendritic cells associated with the expression of IL-1beta, TNF-alpha, GM-CSF, MCP-1 and MIP-2. In vivo depletion experiments showed that rejection of TS/A-IL-12/IL-15 cells required CD8+ T lymphocytes and also involved granulocytes, while CD4+ and NK cells played a minor role. These data show IFN-gamma-independent synergistic anti-tumor effects of IL-12 and IL-15, involving CD8+ cells and secondary chemokines and cytokines, such as TNF-alpha.
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PMID:IFN-gamma-independent synergistic effects of IL-12 and IL-15 induce anti-tumor immune responses in syngeneic mice. 1211 11

We investigated the expression of Th1- and Th2-associated chemokine receptors on peripheral blood lymphocytes at diagnosis and in the first phase of type 1 diabetes. Peripheral blood mononuclear cells (PBMCs) of 25 patients with newly diagnosed type 1 diabetes, 10 patients with longstanding type 1 diabetes, and 35 healthy control subjects were examined for expression of the chemokine receptors CXCR4 (naive T-cells), CCR5 and CXCR3 (Th1 associated), and CCR3 and CCR4 (Th2 associated) on CD3+ lymphocytes. Furthermore, we analyzed chemokine serum levels (monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and RANTES [regulated on activation, normal T-cell expressed and secreted]) and phytohemagglutinin (PHA)-stimulated cytokine secretion of Th1- (gamma-interferon [IFN-gamma] and tumor necrosis factor-alpha [TNF-alpha]) and Th2 (interleukin [IL]-4 and -10)-associated cytokines by PBMC. The patients with newly diagnosed type 1 diabetes were followed for these parameters at 6-12 months after diagnosis. The PBMCs of patients with newly diagnosed but not with longstanding type 1 diabetes showed reduced expression of the Th1-associated chemokine receptors CCR5 (P < 0.001 vs. control subjects) and CXCR3 (P < 0.002 vs. control subjects). This reduction correlated with reduced IFN-gamma and TNF-alpha production of PBMCs after PHA stimulation and reversed 6-12 months after diagnosis to normal levels. CCR4 cells were reduced in both newly diagnosed and longstanding type 1 diabetic patients, which correlated to reduced PHA-stimulated IL-4 production. MIP-1alpha and MIP-1beta levels were considerably elevated in a subgroup of patients with newly diagnosed diabetes. We assume that Th1-associated peripheral T-cells are reduced in a narrow time window at the time of diagnosis of diabetes, possibly due to extravasation in the inflamed pancreas. Thus, chemokine receptor expression of peripheral blood lymphocytes may be a useful surrogate marker for the immune activity of type 1 diabetes (e.g., in intervention trials).
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PMID:Reduced expression of Th1-associated chemokine receptors on peripheral blood lymphocytes at diagnosis of type 1 diabetes. 1214 60

The aim of this article is to review our current understanding of the role of cytokines, chemokines, T cells, Langerhans cells, and neutrophils (PMN) and their interactions in vivo in the host response to Pseudomonas aeruginosa ocular challenge. The cellular/cytokine network in vivo has begun to be unraveled, and the data discussed provide substantive evidence for a regulatory role of CD4(+) T cells (Th1 type) contributing directly to persistence of PMN in the cornea of susceptible C57BL/6 (cornea perforates) versus resistant BALB/c (cornea heals) mice. Additionally, in the susceptible mouse model, CD4(+) T cells interact with Langerhans cells and B7/CD28 ligation appears critical for antigen presentation and the susceptibility response. Various cytokines and chemokines (e.g., MIP-1alpha, IL-1beta, MIP-2, IL-12, and IFN-gamma) and their pattern of sustained upregulation after infection in susceptible versus resistant mice also will be discussed in light of an in vivo cytokine network. T-cell-mediated pathogenic mechanisms are of importance in development of the susceptible response to P. aeruginosa ocular infection. In the absence of T-cell infiltration into the cornea, PMN do not persist in the stroma, and cytokines and chemokines are better balanced, resulting in decreased stromal destruction and the resistance response.
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PMID:Pathogenic mechanisms of P. aeruginosa keratitis: a review of the role of T cells, Langerhans cells, PMN, and cytokines. 1216 40

The complement-derived anaphylatoxin, C5a, is a potent phlogistic molecule that mediates its effects by binding to C5a receptor (C5aR; CD88). We now demonstrate specific binding of radiolabeled recombinant mouse C5a to mouse dermal microvascular endothelial cells (MDMEC) with a K(d50) of 3.6 nM and to approximately 15,000-20,000 receptors/cell. Recombinant mC5a competed effectively with binding of [(125)I]rmC5a to MDMEC. Enhanced binding of C5a occurred, as well as increased mRNA for C5aR, after in vitro exposure of MDMEC to LPS, IFN-gamma, or IL-6 in a time- and dose-dependent manner. By confocal microscopy, C5aR could be detected on surfaces of MDMEC using anti-C5aR Ab. In vitro expression of macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1) by MDMEC was also measured. Exposure of MDMEC to C5a or IL-6 did not result in changes in MIP-2 or MCP-1 production, but initial exposure of MDMEC to IL-6, followed by exposure to C5a, resulted in significantly enhanced production of MIP-2 and MCP-1 (but not TNF-alpha and MIP-1alpha). Although LPS or IFN-gamma alone induced some release of MCP-1 and MIP-2, pre-exposure of these monolayers to LPS or IFN-gamma, followed by addition of C5a, resulted in synergistic production of MIP-2 and MCP-1. Following i.v. infusion of LPS into mice, up-regulation of C5aR occurred in the capillary endothelium of mouse lung, as determined by immunostaining. These results support the hypothesis that C5aR expression on MDMEC and on the microvascular endothelium of lung can be up-regulated, suggesting that C5a in the co-presence of additional agonists may mediate pro-inflammatory effects of endothelial cells.
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PMID:Expression and function of C5a receptor in mouse microvascular endothelial cells. 1242 82

Previous studies with mice have shown that major histocompatibility complex class II (MHC-II) is required for protection from Helicobacter pylori, while MHC-I and antibodies are not. Thus, CD4(+) T cells are presumed to play an essential role in protective immunity via secretion of cytokines. To determine which cytokines are associated with a reduction of bacterial load in immunized mice, gastric cytokine expression was examined by semiquantitative reverse transcription-PCR in protected (defined as > or =2-log-unit decrease in bacterial load) and unprotected mice 4 weeks after challenge. Elevated levels of mRNA for interleukin-12p40 (IL-12p40), gamma interferon (IFN-gamma), tumor necrosis factor alpha, and inducible nitric oxide synthase (iNOS) were associated with protection in immunized-challenged (I/C) mice, but Th2 cytokine (IL-4, IL-5, IL-10, and IL-13) and chemokine (KC, MIP-2, and MCP-1) expression was not associated with protection. Despite the association of IFN-gamma and iNOS message with protection, I/C mice genetically lacking either of these products were able to reduce the bacterial load as well as the wild-type I/C controls. The I/C mice lacking IL-12p40 were not protected compared to unimmunized-challenged mice. All I/C groups developed gastritis. We conclude that neither IFN-gamma nor iNOS is essential for vaccine-induced protection from H. pylori infection. The p40 subunit of IL-12, which is a component of both IL-12 and IL-23, is necessary for protection in immunized mice. These findings suggest a novel IFN-gamma-independent function of IL-12p40 in effective mucosal immunization against H. pylori.
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PMID:Vaccine-induced reduction of Helicobacter pylori colonization in mice is interleukin-12 dependent but gamma interferon and inducible nitric oxide synthase independent. 1254 May 73

A major feature of acute rejection of cardiac allografts is an intense mononuclear cell infiltration accompanied by interferon (IFN)-gamma production. In the current study we tested the role of IFN-gamma in acute rejection of allografts by comparing the histopathology of rejection in wild-type versus IFN-gamma-/- recipients of major histocompatibility complex-mismatched cardiac grafts. Wild-type recipients rejected the allografts at days 8 to 9 after transplant but rejection was accelerated 2 to 3 days in IFN-gamma-deficient recipients. During rejection in wild-type recipients, the allografts were heavily infiltrated with CD8+ T cells and other mononuclear cells. In contrast, allografts in IFN-gamma-deficient recipients had few T cells but an intense neutrophil infiltration accompanied by extensive graft parenchymal necrosis. No difference in expression levels of neutrophil chemoattractants including Groalpha/KC, MIP-2, GCP-2, and MIP-1alpha, was observed in allografts retrieved from wild-type and IFN-gamma-/- recipients. Depletion of neutrophils from IFN-gamma-deficient recipients delayed rejection until days 8 to 10 after transplant and restored the histopathology of acute allograft rejection to that observed in allografts rejected by wild-type recipients. These results indicate the potent regulatory properties of IFN-gamma during acute rejection directed at neutrophil infiltration into allografts and mediating graft tissue necrosis.
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PMID:Neutrophils mediate parenchymal tissue necrosis and accelerate the rejection of complete major histocompatibility complex-disparate cardiac allografts in the absence of interferon-gamma. 1463 37

A significant clinical complication of pulmonary infections with Klebsiella pneumoniae is peripheral blood dissemination, resulting in a systemic infection concurrent with the localized pulmonary infection. In this context, little is known about the role of tumor necrosis factor receptor 1 (TNFR1)-mediated innate immune responses during systemic Klebsiella infections. Mice lacking TNFR1 were significantly more susceptible to Klebsiella-induced mortality following intravenous inoculation. Bacterial clearance was impaired in TNFR1-deficient mice at early times following infection. Unexpectedly, bacterial burdens at the onset of mortality (days 2 to 3 postinfection) were not higher in mice lacking TNFR1. However, elevated production of liver-associated proinflammatory cytokines (interleukin-12, tumor necrosis factor alpha [TNF-alpha[, and gamma interferon [IFN-gamma]) and chemokines (MIP-1 alpha, MIP-2, and MCP-1) was observed within the first 24 h of infection. Additionally, excessive plasma-associated IFN-gamma was also observed late in the course of infection (day 3). Spleen cells from day-3 infected TNFR1-deficient mice secreted markedly enhanced levels of IFN-gamma when cultured in vitro. Additionally, there was a marked increase in the total number of activated lymphocyte subsets as indicated by CD69 upregulation. A notable exception was the sharp decrease in the frequency of splenic NK T cells in infected TNFR1 knockout (KO) mice. Anti-TNF-alpha therapy in TNFR1 KO mice significantly reduced chemokine production and liver injury. Combined, these data indicate a dysregulated antibacterial host response following intravenous Klebsiella infection in the absence of TNFR1 signaling, resulting in heightened cytokine production and hyperactivation of specific splenic lymphocyte subsets.
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PMID:Increased mortality and dysregulated cytokine production in tumor necrosis factor receptor 1-deficient mice following systemic Klebsiella pneumoniae infection. 1293 30

Despite the well-recognized role of adenoviruses of species B in the etiology of severe respiratory disease, the lack of an experimental in vivo model system has limited the understanding of the molecular pathogenesis of species B adenovirus-induced pneumonia. Intratracheal instillation of 5 x 10(8) plaque-forming units (pfu) of adenoviruses 3p and 7h resulted in a robust inflammatory response in the lungs of infected mice. A marked infiltration of neutrophils into the lung air spaces was observed at 1 and 2 days postinfection (dpi), with a concomitant increase in the levels of neutrophil chemokines MIP-2 and KC. The overall histological severity scores were significantly higher for Ad3p-infected mice at 2 dpi, but similar between the two viruses at other time points. Remodeling of the airway epithelia and mucous cell metaplasia were noted in the proximal airways of infected mice, indicating marked epithelial differentiation and/or injury. The proinflammatory cytokines interleukin-beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma [see symbol in text]), and interleukin-12 (IL-12) were induced by viral infection. Expression of the early viral immunomodulatory genes E3-15.3K and E3gp19K mRNA was readily detectable in the lungs of infected mice by reverse transcription-polymerase chain reaction (RT-PCR) at 1 and 2 dpi, coinciding with the peak levels of TNF-alpha. While the detection of gp19K mRNA declined thereafter, 15.3K mRNA was detectable up to 6 dpi. Our results indicate that human Ad3 and Ad7 cause marked pulmonary pathology, inducing similar host responses in the respiratory tract, thus validating the use of the mouse model for the study of early virus-host interactions during lung infection by adenoviruses of subspecies B1.
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PMID:Acute inflammatory response and remodeling of airway epithelium after subspecies B1 human adenovirus infection of the mouse lower respiratory tract. 1293 98

Proper antigen presentation is paramount to the induction of effective and persistent antitumor immune responses. In a murine model of hepatic metastasis of colon cancer, we found that the numbers of in situ mature dendritic cells (DCs) and macrophages in tumor-infiltrating leukocytes (TILs) were significantly increased in mice treated with the combination therapy of herpes simplex virus thymidine kinase, interleukin 2, and GM-CSF genes when compared with control groups without GM-CSF treatment. Significantly higher levels of IFN-gamma, MIP-1 alpha, mIL-12, and GM-CSF were detected in the tumor after the combination therapy. T cells isolated from the combination therapy-treated mice exhibited higher ex vivo direct CTL activity than those from other treatment groups. Antigen-presenting cells (APCs) enriched from the TILs and liver of the combination therapy-treated mice induced higher levels of proliferation by the splenocytes from long-term surviving mice that had been cured of tumors at early time points (days 4 and 7) whereas significant APC activity was only observed in the spleen at the latter time point (day 7, 14) after the combination therapy. In contrast, APCs isolated from tk or tk + IL-2-treated mice did not induce any significant proliferation. Subcutaneous injection of fluorescence-labeled latex microspheres followed by the combination therapy showed a similar sequential trafficking of microspheres, day 4 after the combination therapy to tumor and day 14 to spleen. The results suggest that APCs recruited by intratumoral gene delivery of GM-CSF can capture antigens, mature to a stage suitable for antigen presentation, and subsequently migrate to the spleen where they can efficiently stimulate antigen-specific T cells.
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PMID:In situ recruitment of antigen-presenting cells by intratumoral GM-CSF gene delivery. 1295 80


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