Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation, and some of its bioactivities may involve inflammatory cytokines. Moreover, it may participate in myelopoiesis, either directly or via the induction of cytokines and growth factors. When human monocytes were cultured in the presence of graded concentrations of LTB4, significant stimulation of production of bioactive and immunoreactive interleukin-6 (IL-6) was observed. Nanomolar concentrations of LTB4 were optimal and the LTB4 receptor antagonist LY 255283 could block its activity. The omega-oxidation products of LTB4, 20-OH-LTB4 and 20-COOH-LTB4, were only 22% and 2% effective, respectively. LTA4 was also effective in stimulating IL-6 production, but only at micromolar concentrations, whereas 5-HETE and 12-epi-LTB4 were ineffective. The signaling induced by LTB4 did not seem to involve protein kinase C or A, but rather a tyrosine kinase, as suggested by its inhibition with genistein. LTB4 induced an accumulation of IL-6 messenger RNA (mRNA) in treated monocytes with a dose-response similar to that of IL-6 protein production. Whereas IL-6 mRNA half-life in untreated cells was approximately 1 hour, it was extended to 3 hours in LTB4-treated monocytes. Moreover, nuclear transcription of IL-6 mRNA was augmented at 30 minutes by a factor of 5 in LTB4-treated cells. Pretreatment of cells with cyclohexamide before exposure to LTB4 superinduced IL-6 message expression, but partially inhibited the effect of LTB4 on IL-6 mRNA accumulation, suggesting that newly synthesized proteins may be involved in the transcriptional activation of the IL-6 gene by LTB4. These findings constitute a first demonstration that LTB4 stimulates IL-6 production and that the underlying mechanisms involve both increased IL-6 gene transcription and message stabilization. This may constitute an important mechanism through which rapidly produced mediators may modulate the subsequent production of regulatory or growth-promoting cytokines.
 ...
PMID:Leukotriene B4 enhances interleukin-6 (IL-6) production and IL-6 messenger RNA accumulation in human monocytes in vitro: transcriptional and posttranscriptional mechanisms. 132 42

Human polymorphonuclear granulocytes (PMN) generate the inflammatory mediator leukotriene B4 (LTB4) as a response to cell activation. In addition, PMN inactivate LTB4 by omega-oxidation resulting in the formation of 20-OH- and 20-COOH-LTB4. The transport of exogenous LTB4 to the metabolizing enzymes is mediated via high- and low-affinity receptor subsets. Uptake of [3H]LTB4 by the cells was carried out in a time-dependent fashion, reaching maximal values after 5 min of incubation. No additional uptake of [3H]LTB4 then occurred. Prestimulation of PMN with phorbol myristate acetate or sodium fluoride resulted in the loss of high- and low-affinity receptors. Deactivating concentrations of LTB4 specifically reduced the high-affinity receptor subset. Prestimulation of PMN with cytochalasin B or with the membrane fluidizer butanol shifted the low-affinity receptors to the high-affinity state. The polyene antibiotic amphotericin B shifted high-affinity receptors to the low-affinity subset. The changes in the receptor expression pattern correlated with the respective conversion rate of exogenously added LTB4. Our results suggest that the distribution of high- and low-affinity receptors is regulated by GTP-binding proteins, the activation of protein kinase C and the organization of the membrane bilayer. In this way, human neutrophils control the respective level of the lipid mediator LTB4.
 ...
PMID:Studies on the uptake, binding and metabolism of leukotriene B4 by human neutrophils. 255 70

Leukotriene B4 induced a biphasic change in the cytoplasmic pH of human neutrophils: an initial rapid acidification followed by an alkalinization. The acidification was slightly reduced by the removal of extracellular Ca2+, but the subsequent alkalinization was not. The leukotriene B4-induced alkalinization was dependent on extracellular Na+ and pH, and was inhibited by amiloride and its more potent analogue, 5-(N,N-hexamethylene)amiloride. These characteristics indicate that the cytoplasmic alkalinization is mediated by the Na+-H+ exchange. Oxidation products of leukotriene B4, 20-hydroxyleukotriene B4, 20-carboxyleukotriene B4, and (5S)-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) also stimulated the Na+-H+ exchange, but higher concentrations were required. Treatment of the cells with pertussis toxin inhibited both phases of the leukotriene B4-induced pHi change, while cholera toxin did not affect the pHi change. The alkalinization induced by leukotriene B4 was inhibited by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), an inhibitor of protein kinase C, but was not inhibited by N-(2-guanidinoethyl)-5-isoquinolinesulfonamide which has a less inhibitory effect on protein kinase C. Acidification was not affected by the drugs. These findings suggest that a GTP-binding protein sensitive to pertussis toxin and protein kinase C are involved in the activation of the Na+-H+ exchange stimulated by leukotriene B4.
 ...
PMID:Cytoplasmic pH change induced by leukotriene B4 in human neutrophils. 283 89

Phorbol myristate acetate (PMA), a tumor-promoting phorbol ester, and the calcium ionophore A23187 synergistically induced the noncytotoxic release of leukotriene B4 (LTB4) and other 5-lipoxygenase products of arachidonic acid metabolism from human neutrophils. Whereas neutrophils incubated with either A23187 (0.4 microM) or PMA (1.6 microM) alone failed to release any 5-lipoxygenase arachidonate products, neutrophils incubated with both stimuli together for 5 min at 37 degrees C released LTB4 as well as 20-COOH-LTB4, 20-OH-LTB4, 5-(S),12-(R)-6-trans-LTB4, 5-(S),12-(S)-6-trans-LTB4, and 5-hydroxyeicosatetraenoic acid, as determined by high pressure liquid chromatography. This synergistic response exhibited concentration dependence on both PMA and A23187. PMA induced 5-lipoxygenase product release at a concentration causing a half-maximal effect of approximately 5 nM in the presence of A23187 (0.4 microM). Competition binding experiments showed that PMA inhibited the specific binding of [3H]phorbol dibutyrate ([3H]PDBu) to intact neutrophils with a 50% inhibitory concentration (IC50) of approximately 8 nM. 1-oleoyl-2-acetyl-glycerol (OAG) also acted synergistically with A23187 to induce the release of 5-lipoxygenase products. 4 alpha-phorbol didecanoate (PDD), an inactive phorbol ester, did not affect the amount of lipoxygenase products released in response to A23187 or compete for specific [3H]PDBu binding. PMA and A23187 acted synergistically to increase arachidonate release from neutrophils prelabeled with [3H]arachidonic acid but did not affect the release of the cyclooxygenase product prostaglandin E2. Both PMA and OAG, but not PDD, induced the redistribution of protein kinase C activity from the cytosol to the membrane fraction of neutrophils, a characteristic of protein kinase C activation. Thus, activation of protein kinase C may play a physiologic role in releasing free arachidonate substrate from membrane phospholipids and/or in modulating 5-lipoxygenase activity in stimulated human neutrophils.
 ...
PMID:Phorbol myristate acetate and the calcium ionophore A23187 synergistically induce release of LTB4 by human neutrophils: involvement of protein kinase C activation in regulation of the 5-lipoxygenase pathway. 303 73