Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CXC chemokine, IL-8, is a potent chemoattractant of neutrophils and binds to two distinct receptors, termed IL-8R1 and IL-8R2. These receptors share high affinity for IL-8, however, only IL-8R1 is specific for IL-8 whereas IL-8R2 binds other related chemokines, including GRO alpha with high affinity. Stable Jurkat transfectants were generated expressing either functional IL-8R1 or IL-8R2 (J-IL8R1 and J-IL8R2). Both J-IL8R1 and J-IL8R2 exhibited high affinity IL-8 binding (Kd 3-5 nM) with respective receptor densities of 23,000 +/- 3,000 and 18,500 +/- 1,500. Pre-treatment of both transfectants with 1.0 micrograms/ml B. pertussis toxin (PTx) resulted in inhibition of IL-8 mediated intracellular Ca2+ mobilisation and chemotaxis, without altering the receptor's affinity for its ligand. This indicates that both receptors couple to a PTx-sensitive G-protein. Further studies showed that IL-8R1 and IL-8R2 could mediate time-dependent phosphorylation of p42/p44 MAP-kinase. In both transfectants, phosphorylation was maximal at 1-2 min after IL-8 stimulation and could be inhibited by PTx. Stimulation of J-IL8R1 and J-IL8R2 with GRO alpha revealed that this chemokine was a more potent activator of MAP-kinase in J-IL8R2, an observation reflected in the high affinity binding of GRO alpha to IL-8R2. These studies indicate that chemokines are capable of activating protein kinases and with regards to PTx-sensitivity and MAP-kinase stimulation, no significant differences between IL-8R1 and IL-8R2 post-receptor signalling occur during cell activation by IL-8.
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PMID:A comparison of post-receptor signal transduction events in Jurkat cells transfected with either IL-8R1 or IL-8R2. Chemokine mediated activation of p42/p44 MAP-kinase (ERK-2). 775 May 73

CXC chemokine receptor 4 (CXCR4) is a co-receptor for human immunodeficiency virus (HIV) infection and is believed to be involved in the pathogenesis of AIDS-associated neurologic disorders and brain tumors. The physiological roles of CXCR4 in developmental patterning of the nervous and hematopoietic system; gastrointestinal angiogenesis; and cardiac organogenesis were established by studies in gene-targeted mice. Studies on CXCR4 expression and regulation in neuroepithelial cells are fundamental for understanding its physiopathologic roles in the central nervous system (CNS). We show here that CXCR4 expression by primary mouse astrocytes is suppressed by exposure to tumor necrosis factor-alpha (TNF-alpha). TNF-alpha caused a pronounced down-regulation of CXCR4 mRNA in a dose- and time-dependent manner. TNF-alpha-mediated decrease of CXCR4 mRNA accumulation resulted in decreased CXCR4 protein expression. As a result, the ability of stromal cell-derived factor-1alpha (SDF-1alpha) to induce activation of MAP kinases, Erk1/2 was impaired. The half life of CXCR4 mRNA in the presence and absence of TNF-alpha stimulation was comparable, suggesting that TNF-alpha down-regulated CXCR4 mRNA at the transcriptional level. These results suggest that TNF-alpha could modulate HIV and brain tumor pathogenesis and immune-mediated inflammation in the central nervous system (CNS) by regulation of CXCR4 expression.
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PMID:TNF-alpha down-regulates CXCR4 expression in primary murine astrocytes. 1114 46

Ceramide is recognized as an antiproliferative and proapoptotic sphingolipid metabolite; however, the role of ceramide in inflammation is not well understood. To determine the role of C6-ceramide in regulating inflammatory responses, human corneal epithelial cells were treated with C6-ceramide in 80 nm diameter nanoliposome bilayer formulation (Lip-C6) prior to stimulation with UV-killed Staphylococcus aureus. Lip-C6 (5 muM) inhibited the phosphorylation of proinflammatory and proapoptotic MAP kinases JNK and p38 and production of neutrophil chemotactic cytokines CXCL1, CXCL5, and CXCL8. Lip-C6 also blocked CXC chemokine production by human and murine neutrophils. To determine the effect of Lip-C6 in vivo, a murine model of corneal inflammation was used in which LPS or S. aureus added to the abraded corneal surface induces neutrophil infiltration to the corneal stroma, resulting in increased corneal haze. Mice were treated topically with 2 nMoles (811 ng) Lip-C6 or with control liposomes prior to, or following, LPS or S. aureus stimulation. We found that corneal inflammation was significantly inhibited by Lip-C6 but not control liposomes given prior to, or following, activation by LPS or S. aureus. Furthermore, Lip-C6 did not induce apoptosis of corneal epithelial cells in vitro or in vivo, nor did it inhibit corneal wound healing. Together, these findings demonstrate a novel, anti-inflammatory, nontoxic, therapeutic role for liposomally delivered short-chain ceramide.
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PMID:Inhibition of corneal inflammation by liposomal delivery of short-chain, C-6 ceramide. 1837 42

Once activated by an infected pathogen, dendritic cells (DC's) migrate toward secondary lymphoid organs, and release inflammatory mediators. Therefore, in some case, mature DC's (mDC's) are considered to be potent inflammatory inducers. In this study we demonstrated that histone acetylation plays an important regulatory role in conserving the migration activity of the DC's. We showed that histone deacetylase (HDAC) inhibition reduces CXC chemokine receptor 4 (CXCR4)-dependent DC's migration. These inhibitory effects were found to be caused by a reduction in the expression of CXCR4, and by the phosphorylation of p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinases 1 and 2 (ERK 1/2), and c-Jun N-terminal kinase (JNK). Taken together, histone deacetylase inhibitors (HDACi's) inhibit the phosphorylation of MAP kinases, and this inhibition reduces the expression of CXCR4, and this reduction decreases the chemotactic activity of mDC's.
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PMID:Histone deacetylase inhibitors suppress CXCR4-mediated dendritic cell migration by regulation of maturation process. 2397 79