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)

It is well established that cytokines can induce the production of chemokines, but the role of chemokines in the regulation of cytokine expression has not been fully investigated. Exposure of rat cardiac-derived endothelial cells (CDEC) to lipopolysaccharide-induced CXC chemokine (LIX), and to a lesser extent to KC and MIP-2, activated NF-kappaB and induced kappaB-driven promoter activity. LIX did not activate Oct-1. LIX-induced interleukin-1beta and tumor necrosis factor-alpha promoter activity, and up-regulated mRNA expression. Increased transcription and mRNA stability both contributed to cytokine expression. LIX-mediated cytokine gene transcription was inhibited by interleukin-10. Transient overexpression of kinase-deficient NF-kappaB-inducing kinase (NIK) and IkappaB kinase (IKK), and dominant negative IkappaB significantly inhibited LIX-mediated NF-kappaB activation in rat CDEC. Inhibition of G(i) protein-coupled signal transduction, poly(ADP-ribose) polymerase, phosphatidylinositol 3-kinase, and the 26 S proteasome significantly inhibited LIX-mediated NF-kappaB activation and cytokine gene transcription. Blocking CXCR2 attenuated LIX-mediated kappaB activation and kappaB-driven promoter activity in rat CDEC that express both CXCR1 and -2, and abrogated its activation in mouse CDEC that express only CXCR2. These results indicate that LIX activates NF-kappaB and induces kappaB-responsive proinflammatory cytokines via either CXCR1 or CXCR2, and involved phosphatidylinositol 3-kinase, NIK, IKK, and IkappaB. Thus, in addition to attracting and activating neutrophils, the ELR(+) CXC chemokines amplify the inflammatory cascade, stimulating local production of cytokines that have negative inotropic and proapoptotic effects.
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PMID:Chemokine-cytokine cross-talk. The ELR+ CXC chemokine LIX (CXCL5) amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B pathway. 1246 47

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

Activation of innate immunity in the lungs can lead to a self-limited inflammatory response or progress to severe lung injury. We investigated whether specific parameters of NF-kappaB pathway activation determine the outcome of acute lung inflammation using a novel line of transgenic reporter mice. Following a single i.p. injection of Escherichia coli LPS, transient NF-kappaB activation was identified in a variety of lung cell types, and neutrophilic inflammation resolved without substantial tissue injury. However, administration of LPS over 24 h by osmotic pump (LPS pump) implanted into the peritoneum resulted in sustained, widespread NF-kappaB activation and neutrophilic inflammation that culminated in lung injury at 48 h. To determine whether intervention in the NF-kappaB pathway could prevent progression to lung injury in the LPS pump model, we administered a specific IkappaB kinase inhibitor (BMS-345541) to down-regulate NF-kappaB activation following the onset of inflammation. Treatment with BMS-345541 beginning at 20 h after osmotic pump implantation reduced lung NF-kappaB activation, concentration of KC and MIP-2 in lung lavage, neutrophil influx, and lung edema measured at 48 h. Therefore, sustained NF-kappaB activation correlates with severity of lung injury, and interdiction in the NF-kappaB pathway is beneficial even after the onset of lung inflammation.
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PMID:Duration and intensity of NF-kappaB activity determine the severity of endotoxin-induced acute lung injury. 1688 59

Cigarette smoke (CS) induces abnormal and sustained lung inflammation; however, the molecular mechanism underlying sustained inflammation is not known. It is well known that activation of I kappaB kinase beta (IKK beta) leads to transient translocation of active NF-kappaB (RelA/p65-p50) in the nucleus and transcription of pro-inflammatory genes, whereas the role of IKK alpha in perpetuation of sustained inflammatory response is not known. We hypothesized that CS activates IKK alpha and causes histone acetylation on the promoters of pro-inflammatory genes, leading to sustained transcription of pro-inflammatory mediators in mouse lung in vivo and in human monocyte/macrophage cell line (MonoMac6) in vitro. CS exposure to C57BL/6J mice resulted in activation of IKK alpha, leading to phosphorylation of ser10 and acetylation of lys9 on histone H3 on the promoters of IL-6 and MIP-2 genes in mouse lung. The increased level of IKK alpha was associated with increased acetylation of lys310 RelA/p65 on pro-inflammatory gene promoters. The role of IKK alpha in CS-induced chromatin modification was confirmed by gain and loss of IKK alpha in MonoMac6 cells. Overexpression of IKK alpha was associated with augmentation of CS-induced pro-inflammatory effects, and phosphorylation of ser10 and acetylation of lys9 on histone H3, whereas transfection of IKK alpha dominant-negative mutants reduced CS-induced chromatin modification and pro-inflammatory cytokine release. Moreover, phosphorylation of ser276 and acetylation of lys310 of RelA/p65 was augmented in response to CS extract in MonoMac6 cells transfected with IKK alpha. Taken together, these data suggest that IKK alpha plays a key role in CS-induced pro-inflammatory gene transcription through phospho-acetylation of both RelA/p65 and histone H3.
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PMID:IKK alpha causes chromatin modification on pro-inflammatory genes by cigarette smoke in mouse lung. 1823 89

Inflammatory bowel disease arises from the interplay between luminal bacteria and the colonic mucosa. Targeted inhibition of pro-inflammatory pathways without global immunosuppression is highly desirable. Apolipoprotein (apo) E has immunomodulatory effects and synthetically derived apoE-mimetic peptides are beneficial in models of sepsis and neuroinflammation. Citrobacter rodentium is the rodent equivalent of enteropathogenic Escherichia coli, and it causes colitis in mice by colonizing the surface of colonic epithelial cells and inducing signaling events. We have reported that mice deficient in inducible nitric-oxide (NO) synthase (iNOS) have attenuated C. rodentium-induced colitis. We used young adult mouse colon (YAMC) cells that mimic primary colonic epithelial cells to study effects of an antennapedia-linked apoE-mimetic peptide, COG112, on C. rodentium-activated cells. COG112 significantly attenuated induction of NO production, and iNOS mRNA and protein expression, in a concentration-dependent manner. COG112 inhibited the C. rodentium-stimulated induction of iNOS and the CXC chemokines KC and MIP-2 to the same degree as the NF-kappaB inhibitors MG132 or BAY 11-7082, and there was no additive effect when COG112 and these inhibitors were combined. COG112 significantly reduced nuclear translocation of NF-kappaB, when assessed by electromobility shift assay, immunoblotting, and immunofluorescence for p65. This correlated with inhibition of both C. rodentium-stimulated IkappaB-alpha phosphorylation and degradation, and IkappaB kinase activity, which occurred by inhibition of IkappaB kinase complex formation rather than by a direct effect on the enzyme itself. These studies indicate that apoE-mimetic peptides may have novel therapeutic potential by inhibiting NF-kappaB-driven proinflammatory epithelial responses to pathogenic colonic bacteria.
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PMID:The apolipoprotein E-mimetic peptide COG112 inhibits the inflammatory response to Citrobacter rodentium in colonic epithelial cells by preventing NF-kappaB activation. 1841 77

Lysophosphatidic acid (LPA) is a potent agonist that exerts various cellular functions on many cell types through binding to its cognate G protein-coupled receptors (GPCRs). Although LPA induces NF-kappaB activation by acting on its GPCR receptor, the molecular mechanism of LPA receptor-mediated NF-kappaB activation remains to be well defined. In the present study, by using MEKK3-, TAK1-, and IKKbeta-deficient murine embryonic fibroblasts (MEFs), we found that MEKK3 but not TAK1 deficiency impairs LPA and protein kinase C (PKC)-induced IkappaB kinase (IKK)-NF-kappaB activation, and IKKbeta is required for PKC-induced NF-kappaB activation. In addition, we demonstrate that LPA and PKC-induced IL-6 and MIP-2 production are abolished in the absence of MEKK3 but not TAK1. Together, our results provide the genetic evidence that MEKK3 but not TAK1 is required for LPA receptor-mediated IKK-NF-kappaB activation.
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PMID:MEKK3 is required for lysophosphatidic acid-induced NF-kappaB activation. 1946 15