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)

Results from previous studies indicate that hyperthyroidism increases the risk of ozone-induced lung toxicity. To better understand the processes that might contribute to the increased pulmonary inflammatory response to ozone in hyperthyroidism, we evaluated bronchoalveolar lavage fluid levels of selected cytokines in control and hyperthyroid rats after exposure to air or ozone. In addition, we assessed whether there is a relative increase in nuclear factor-kappa B (NF-kappaB) binding activity in cells harvested by bronchoalveolar lavage from hyperthyroid rats following the inhalation of ozone. A hyperthyroid condition was induced by the administration of thyroxine (0.5 mg/kg body weight) for 7 days. Control rats received vehicle injections. The animals were then exposed by inhalation to air or ozone (2 ppm for 3 h) and studied 18 h following the exposure. Bronchoalveolar lavage levels of MIP-2 and MCP-1 were increased in both control and hyperthyroid rats by ozone exposure. However, the increases in hyperthyroid rats were much greater, MIP-2 1.5-fold and MCP-1 11-fold, when compared to levels in controls following ozone. These changes appeared to be relatively specific; bronchoalveolar lavage fluid levels of interleukin (IL)-6, IL-4, and IL-10 were generally low or nondetectable across all of the studied groups at the 18-h postexposure time point. We also found that NF-kappaB binding activity was increased at both 4 and 18 h following ozone exposure in bronchoalveolar lavage cell extracts from hyperthyroid rats relative to the activity in control samples. Collectively, these results suggest that mechanisms contributing to the enhanced pulmonary inflammatory response to ozone in a hyperthyroid state include an increase in NF-kappaB activation and an upregulation of chemokine production.
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PMID:Influence of hyperthyroidism on rat lung cytokine production and nuclear factor-kappaB activation following ozone exposure. 1245 97

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

Pseudomonas aeruginosa is a pathogen that frequently causes acute lung injury, bacteremia and sepsis in critically ill patients. As tissue macrophages are a major producer of inflammatory mediators that contribute to septic physiology, and are essential for eliminating bacteria from the circulation, we investigated the role of tissue macrophages in the generation of both inflammatory and anti-inflammatory cytokines in septic shock by using our mouse model of P. aeruginosa pneumonia. To see the effects of tissue macrophage depletion, we intravenously injected dichloromethylene-diphosphonate (Cl2MDP)-encapsulating liposomes in mice. Two days after the liposome injection, we instilled cytotoxic P. aeruginosa (PA103) into the lung that disseminates and causes septic shock. After the infection, we collected blood and bronchoalveolar lavage fluids. The samples were then analyzed for TNF-alpha, MIP-2, and IL-10 concentration. We compared these results to control mice that received either liposomes without Cl2MDP or phosphate buffered saline alone. Plasma TNF-alpha, MIP-2, and IL-10 levels were significantly decreased in the tissue macrophage-depleted mice compared to the control groups of mice. Although depletion of tissue macrophages by Cl2MDP-liposome administration did not affect the severity of bacteremia or the survival of infected mice, these results imply that tissue macrophages have a major role in the production of both proinflammatory and anti-inflammatory cytokines in the circulation and in the causing septic physiology associated with P. aeruginosa pneumonia.
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PMID:Effects of Cl2MDP-encapsulating liposomes in a murine model of Pseudomonas aeruginosa-induced sepsis. 1260 29

Prior studies have shown that hemorrhage (Hem) can serve as a priming stimulus for acute lung injury (ALI) triggered by subsequent septic challenge (cecal ligation and puncture, CLP). Furthermore, we have reported that in vivo antibody neutralization of the chemokines, macrophage inflammatory chemokine-2 (MIP-2) and keratinocyte-derived chemokine (KC), immediately after Hem appears to differentially effect the onset of ALI. However, although we hypothesize that this is due to divergent effects of MIP-2 and KC on Hem-induced neutrophil (PMN) priming, this has not been tested. To examine this hypothesis, PMN donor mice were Sham-Hem or Hem for 90 min at 35 +/- 5 mmHg and were then administered anti-MIP- 2 (Hem/anti-MIP2), anti-KC (Hem/anti-KC), or nonspecific immunoglobulin (Ig) G (Hem/IgG) during resuscitation (Ringer's lactate = four times the amount of drawn blood volume). Twenty-four hours post-Hem, the peripheral blood PMN were purified from these donor animals and were introduced into PMN-depleted recipient mice [depleted by prior anti-Gr1 (mouse PMN-specific marker) antibody treatment]. One hour after PMN transfer, recipient mice were subjected to CLP, euthanized 24 h later, and plasma as well as lung tissue samples were collected. PMN influx was assessed by myeloperoxidase assay (MPO; microU/mg protein) and histologically (IL-6, MIP-2, KC, and IL-10 levels) by enzyme-linked immunoabsorbant assay (ELISA; ng/mg). The results show that donor PMN from Hem/IgG but not Sham-Hem mice produce increased PMN influx (increased MPO, increased % esterase+ cells in tissue) into the lung and local tissue inflammation (increased IL-6/MIP-2, decreased IL-10) in PMN-depleted CLP recipient mice, which was attenuated in mice receiving cells from Hem/anti-MIP-2 but not Hem/anti-KC treated donors. Interestingly, although Hem/anti-MIP-2 donor PMN produced comparable effects on blood IL-6/MIP-2 levels, they were ineffective in altering the change in plasma IL-10/KC levels induce by Hem. Taken together, these data demonstrate that Hem-induced priming of PMN not only mediates ALI in the mouse, but also that this process is differentially effected by MIP2 and KC, despite the fact that both signal through CXCR2.
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PMID:Differential effects of macrophage inflammatory chemokine-2 and keratinocyte-derived chemokine on hemorrhage-induced neutrophil priming for lung inflammation: assessment by adoptive cells transfer in mice. 1268 48

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of HIV disease. Exposure of human macrophages to HHV-6A or HHV-6B profoundly impaired their ability to produce interleukin 12 (IL-12) upon stimulation with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). By contrast, the production of tumor necrosis factor-alpha (TNF-alpha); regulated on activation, normal T-cell expressed and secreted (RANTES); and macrophage inflammatory protein 1 beta (MIP-1 beta) was not negatively affected. To exclude the involvement of IL-12-suppressive cytokines, such as IL-10 and TNF-alpha, the viral stocks were fractionated by ultra-centrifugation. The bulk of the suppressive activity was recovered within the virion-rich pelleted fraction that was virtually devoid of such cytokines. IL-12 suppression was independent of viral replication, and the effect was not abrogated upon ultraviolet-light inactivation of the viral inoculum. The mechanism of HHV-6-mediated IL-12 suppression was investigated by RNase protection assays, which demonstrated unaltered levels of IL-12 p35 mRNA and only a modest reduction in p40 mRNA, which was insufficient to account for the near-complete loss of both extracellular and intracellular IL-12 protein. Moreover, both the IFN-gamma and the LPS signaling pathways were intact in HHV-6-treated cells. These data suggest that HHV-6 can dramatically affect the generation of effective cellular immune responses, providing a novel potential mechanism of HHV-6-mediated immunosuppression.
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PMID:Selective suppression of IL-12 production by human herpesvirus 6. 1282

Infection of mice with Leishmania major results in disease progression or resolution, largely depending on the genetic backgrounds of the mouse strains. Infection with Leishmania amazonensis, on the other hand, causes progressive cutaneous lesions in most inbred strains of mice. We hypothesized that deficient activation of early immune responses contributes to the pathogenesis in L. amazonensis-infected mice. To distinguish early molecular events that determine the outcome of Leishmania infections, we examined cytokine gene expression in C57BL/6 mice infected with either L. amazonensis or L. major (a healing model). After 2 to 4 weeks, L. amazonensis-infected mice had significantly delayed and depressed expression of inflammatory cytokines (interleukin-12 [IL-12], gamma interferon, IL-1 alpha, IL-1 beta), CC chemokines (CC chemokine ligand 3 [CCL3]/macrophage inflammatory protein 1 alpha [MIP-1 alpha], CCL4/MIP-1 beta, CCL5/RANTES, MIP-2), and chemokine receptors (CCR1, CCR2, CCR5) in foot tissues and draining lymph nodes compared to the expression in L. major-infected controls. These findings correlated with defective T-cell responsiveness to parasite stimulation in vivo and in vitro. Adoptive transfer of L. amazonensis-specific Th1 cells prior to infection overcame the immune defects of the animals, leading to complete control of the disease. Studies with gene knockout mice suggested that IL-10, but not IL-4, contributed partially to compromised immunity in L. amazonensis-infected hosts. The data suggest that there is impairment in multiple immune functions at early stages of infection with L. amazonensis parasites and provide a compelling rationale to explore immune augmentation as an intervention in American cutaneous leishmaniasis.
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PMID:Impaired expression of inflammatory cytokines and chemokines at early stages of infection with Leishmania amazonensis. 1287 3

Cytokines play a central role in the pathogenesis of allergic diseases and allergic inflammation. Therefore, an understanding of mechanisms which regulate production and function of cytokines is very important and may result in the development of more effective methods of treatment of allergic diseases. Recent studies have demonstrated that the induction of allergic inflammation requires genetic background and environmentak factors. The most important cytokines and chemokines are IL-4, IL-5, IL-3, IL-13, GM-CSF and TNF-alpha. Many other cytokines are responsible for the growth, maturity, migration activation and apoptosis of all cells involved in allergic inflammation, among them are IL-2, IL-5, IL-6, IL-9, MIP-1 alpha, RANTES, IL-8, IL-12, IL-18, IFN-alpha i gamma, TGF-beta, sIL-4, IL-1Ra. Recently it has been proven that IL-10 and other cytokines from the IL-10 family, and TGF-beta have anti-inflammatory properties in allergy.
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PMID:[Cytokines in allergic inflammation]. 1452 54

We have characterized leukocyte migration to the pleural cavity in a methylated-BSA (mBSA)-induced model of murine delayed-type hypersensitivity and evaluated the ability of IL-4 and IL-10 to modulate this response. Neutrophils, macrophages, T cells, and dendritic cells migrated to the pleural cavity in a time-dependent fashion following direct intrapleural antigen challenge, with neutrophils comprising the majority of exudate leukocytes in the cavity within the first 24 h and the number of mononuclear cells increasing at later times. Real-time quantitative PCR analysis of infiltrating leukocytes revealed a marked elevation of steady-state mRNA levels of IL-1beta and TNFalpha and the chemokines KC, MIP-2, CXCL9, CXCL10, CXCL11, CCL2, CCL3, and CCL4 at 6 h postchallenge, which diminished over time. In contrast, gammaIFN mRNA levels were maximal at 24 h and CCL5 expression was sustained throughout 72 h. ELISA analysis of pleural exudate fluid revealed significant elevations of KC and CCL2 protein levels at 6 h postantigen challenge and a peak increase in gammaIFN protein at 24 h, confirming our mRNA observations. Administration of recombinant murine IL-4 or IL-10 prior to challenge significantly blocked cell trafficking to the pleural cavity as well as peak levels of exudate gammaIFN, with IL-4 being more potent in impairing these responses. IL-4 administration also increased the proportion of naive T cells in the pleural cavity, as judged by CD62L and CD45RB expression. These results indicate that this in vivo model demonstrates a pattern of events associated with Th1-mediated leukocyte trafficking and underscore the potential utility of this in vivo model for evaluating therapeutic inhibitors of leukocyte trafficking.
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PMID:Impairment of leukocyte trafficking in a murine pleuritis model by IL-4 and IL-10. 1452 70

Nuclear factor kappa B (NF-kappaB) is a transcription factor pivotal for the development of inflammation. A dysregulation of NF-kappaB has been shown to play an important role in many chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and psoriasis. Although classical NF-kappaB, a heterodimer composed of the p50 and p65 subunits, has been well studied, little is known about gene regulation by other hetero- and homodimeric forms of NF-kappaB. While p65 possesses a transactivation domain, p50 does not. Indeed, p50/p50 homodimers have been shown to inhibit transcriptional activity. We have recently shown that Interleukin-10 exerts its anti-inflammatory activity in part through the inhibition of NF-kappaB by blocking IkappaB kinase activity and by inhibiting NF-kappaB already found in the nucleus. Since the inhibition of nuclear NF-kappaB could not be explained by an increase of nuclear IkappaB, we sought to further investigate the mechanisms involved in the inhibition of NF-kappaB by IL-10. We show here that IL-10 selectively induced nuclear translocation and DNA-binding of p50/p50 homodimers in human monocytic cells. TNF-alpha treatment led to a strong translocation of p65 and p50, whereas pretreatment with IL-10 followed by TNF-alpha blocked p65 translocation but did not alter the strong translocation of p50. Furthermore, macrophages of p105/p50-deficient mice exhibited a significantly decreased constitutive production of MIP-2alpha and IL-6 in comparison to wild type controls. Surprisingly, IL-10 inhibited high constitutive levels of these cytokines in wt macrophages but not in p105/p50 deficient cells. Our findings suggest that the selective induction of nuclear translocation and DNA-binding of the repressive p50/p50 homodimer is an important anti-inflammatory mechanism utilized by IL-10 to repress inflammatory gene transcription.
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PMID:Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50. 1467 66

We investigated the effect of high VT ventilation on adult and newborn rats by examining pulmonary injury and cytokine messenger RNA (mRNA). On the basis of compliance, edema formation, and histology, ventilation with 25 ml.kg(-1) was more injurious to adult rats than newborns. Ventilation with 40 ml kg(-1) minimally affected compliance in newborns but caused death in adults. Ventilation of adults for 30 minutes at 25 ml kg(-1) upregulated the mRNA expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-2 (MIP-2), and IL-10, whereas in newborns such ventilation only increased mRNA expression of MIP-2 and IL-10. When VT was raised to 40 ml kg(-1) in newborns, IL-1beta mRNA levels were additionally increased at 30 minutes, whereas ventilation for 3 hours additionally increased IL-6 and TNF-alpha mRNA. In newborns, the addition of 100% oxygen (O2) to 30 minutes of ventilation blunted the high VT induction of IL-1beta, IL-10, and MIP-2 mRNA expressions, whereas at 3 hours, 100% O2 concentration synergistically increased the mRNAs for TNF-alpha and IL-6. Overall, adult rats are more susceptible to high VT-induced lung injury compared with newborns. In newborns, the inflammatory response is dependent on VT, duration, and supplemental O2. Thus, recommendations for VT limitation based on adult data may be inappropriate for newborns.
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PMID:High tidal volume ventilation causes different inflammatory responses in newborn versus adult lung. 1471 97


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