Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We reported previously that bone marrow granulocytes respond to small amounts of enterobacterial lipopolysaccharide (LPS) via a CD14-independent and TLR4-mediated mechanism by de novo expression of an inducible receptor (CD14) and by down-modulation of a constitutive receptor (L-selectin). In this report we address another effect of LPS: the down-regulation of receptors for tumor necrosis factor-alpha. In mouse bone marrow cells (BMC), this down-regulation is detectable soon (20 min) after exposure of the cells to low levels (0.5 ng/ml) of LPS. This temperature-dependent effect is rather selective for LPS and requires the presence of a conventional lipid A structure in the LPS molecule and a functional TLR4 molecule in the cells. The down-modulation, due to a shedding of the receptors, is blocked by p38 MAPK inhibitors, by a furin inhibitor, and by three metalloproteinase inhibitors (BB-3103, TIMP-2, and TIMP-3). In contrast, inhibitors of MEK, protein kinase C, cAMP-dependent protein kinase, and kinases of the Src family do not block the shedding. Analysis of BMC from mice lacking tumor necrosis factor receptor-1 (CD120a-/-) or tumor necrosis factor receptor-2 (CD120b-/-) indicates that the LPS-induced shedding is specific for CD120b. Thus, exposure of BMC to LPS triggers a rapid shedding of CD120b via a protein kinase C- and Src-independent pathway mediated by p38 MAPK, furin, and metalloproteinase. The additive effects of furin and metalloproteinase inhibitors suggest that these enzymes are involved in parallel shedding pathways.
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PMID:TLR4-dependent lipopolysaccharide-induced shedding of tumor necrosis factor receptors in mouse bone marrow granulocytes. 1266 67

This study examines the role of 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and the natural compound, bryostatin-1, on the monocytic differentiation of NB4 acute promyelocytic leukemia cells. We previously showed that 1,25(OH)(2)D(3) primes NB4 cells to mature along the monocyte/macrophage pathway in response to the tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). This maturation response involves protein kinase C (PKC) signaling, activation of the transcription factor nuclear factor kappaB (NFkB), and intracellular calcium and calpain activity. The natural compound, bryostatin-1, exhibits some of the effects of TPA but lacks its tumor-promoting nature. 1,25(OH)(2)D(3) treatment followed by bryostatin-1 induces monocytic differentiation of NB4 cells, however,this effect is less pronounced than the combination of 1,25(OH)(2)D(3) and TPA. Maturation is accompanied by decreased proliferation, changes in cellular morphology, increased plastic adherence, and expression of the cell surface marker CD14. Changes in the cell cycle traverse occur before the morphological and biochemical changes associated with differentiation. Within 24 h of bryostatin-1 addition, NB4 cells begin arresting, predominantly in G(1) phase. Changes in the cell cycle traverse were accompanied by changes in the expression of several cell cycle regulatory proteins. Combination 1,25(OH)(2)D(3) and bryostatin-1 treatment, resulted in decreased expression of the cyclin-dependent kinases Cdk2, Cdk1, and Cdk4, of cyclins E and D3, and of the retinoblastoma binding protein (RBBP). Levels of the cyclin-dependent kinase inhibitors p21 and p27 as well as Cyclin D1 were undetectable in NB4 cell lysates, suggesting that they do not participate in the differentiation response or cell cycle control in this model.
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PMID:1alpha,25-dihydroxyvitamin D3 and bryostatin-1 synergize to induce monocytic differentiation of NB4 acute promyelocytic leukemia cells by modulating cell cycle progression. 1498 May 23

In the present study, we investigated the in vitro effect of saucernetin-7, which is a dineolignan isolated from Saururus chinensis, on the proliferation, cell cycle-regulation and differentiation of HL-60 human promyelocytic leukemia cells. Saucernetin-7 potently inhibited the proliferation of HL-60 cells in both a dose- and time-dependent manner with an IC50, approximately 5 microM. DNA flow-cytometry indicated that saucernetin-7 markedly induced a G1 phase arrest of HL-60 cells. Among the G1 phase cell cycle-related proteins, the levels of cyclin-dependent kinase (CDK)6 and cyclin D1 were reduced by saucernetin-7, whereas the steady-state levels of CDK2, CDK4, cyclin D2, cyclin D3 and cyclin E were unaffected. The protein and mRNA levels of a CDK inhibitor p21CIP1/WAF1, but not p27KIP1, were markedly increased by saucernetin-7 and p21CIP1/WAF1 induction is likely to occur at the transcriptional level because actinomycin D blocked this induction. In addition, saucernetin-7 markedly enhanced the binding of p21CIP1/WAF1 with CDK2 and CDK6, resulting in the reduced activity of both kinases and the hypophosphorylation of Rb protein. We furthermore suggest that saucernetin-7 is a potent inducer of the differentiation of HL-60 cells, based on observations such as a reduction of the nitroblue tetrazolium level, an increase in the esterase activities and phagocytic activity, morphology changes, and the expression of CD14 and CD66b surface antigens. In conclusion, the onset of saucernetin-7-induced the G0/G1 arrest of HL-60 cells prior to the differentiation is linked to a sharp up-regulation of the p21CIP1/WAF1 level and a decrease in the CDK2 and CDK6 activities. This is the first report demonstrating that saucernetin-7 potently inhibits the proliferation of human promyelocytic HL-60 cells via the G1 phase cell cycle arrest and differentiation induction.
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PMID:Saucernetin-7 isolated from Saururus chinensis inhibits proliferation of human promyelocytic HL-60 leukemia cells via G0/G1 phase arrest and induction of differentiation. 1503 3

Betulinic acid (BA) is a pentacyclic triterpene found in a number of medicinal plants and has been shown to cause apoptosis in a number of cell lines. We report here that BA may also have an effect on HL-60 cell differentiation. BA was cytotoxic to HL-60 cells with an IC50 of 5.7 microM after a 72-h treatment. Flow cytometry analysis showed that after exposure to 1-12 microM of BA for 72 h, approximately 10% of viable cells were in the sub-G1, presumably apoptotic, phase. At the same time differentiation was induced in approximately 10% (at 1 microM BA) to a maximum of 20% (at 6 microM BA) of cells as judged by the NBT-reduction test, and the expression of membrane markers CD11b and CD14. On the other hand, at 1 and 5 nM, 1alpha,25-dihydroxyvitamin D3 (DHD3) induced differentiation in approximately 10 and 70% of cells, respectively. At 1 nM DHD3, the addition of 1 microM BA increased differentiated cells from 10 to 43% and with 3 microM BA the increase was to 80%. BA also enhanced the effects of DHD3 in the expansion of the G1 cell population with a concomitant decrease of S phase cells. The effects of DHD3 and BA on CD11b and CD14 expression were inhibited by PD98059, a MEK inhibitor. Our results suggest that BA may enhance the effect of DHD3 in inducing mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase-mediated HL-60 cell differentiation.
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PMID:Betulinic acid enhances 1alpha,25-dihydroxyvitamin D3-induced differentiation in human HL-60 promyelocytic leukemia cells. 1520 7

The protein-bound polysaccharide isolated from basidiomycetes (PSK) is a biological response modifier capable of exhibiting various biological activities, such as antitumor and antimicrobial effects. In the present study, we found that PSK suppressed interleukin (IL)-6 production in murine peritoneal macrophages stimulated with endotoxic lipopolysaccharide (LPS) and its synthetic lipid A (compound 506). Nitric oxide production and p38 mitogen-associated protein kinase phosphorylation induced in a murine macrophage cell line, J774-A1, by LPS and compound 506 were also inhibited by PSK. Further, PSK distinctly suppressed nuclear factor-kappaB activation in Ba/F3 cells expressing mouse Toll-like receptor 4 and MD-2, following stimulation with LPS and compound 506, however, not with Taxol. These PSK-induced inhibitory activities were caused by inhibition of the physical associations of LPS with LPS-binding protein (LBP) and CD14. PSK also protected mice from LPS-induced lethality, presumably by down-regulating IL-6 and tumor necrosis factor-alpha concentrations in serum. These findings indicate that PSK, which also has an ability to regulate LBP/CD14 functions, may be useful for clinical control of endotoxic sepsis.
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PMID:Protein-bound polysaccharide isolated from basidiomycetes inhibits endotoxin-induced activation by blocking lipopolysaccharide-binding protein and CD14 functions. 1560 41

Mice on the CBA inbred strain background expressing the well characterized mutation designated xid in the cytoplasmic signalling enzyme Bruton's protein kinase have been previously noted to illustrate shifts in T helper type 1 (Th1)/Th2 immunity which is underlined by an apparent failure to produce the regulatory cytokine interleukin-10. In the current study we examined if this extended to infection with Mycobacterium tuberculosis, which also depends on Th1 immunity. Contrary to expectations, xid mice showed evidence of a transient early susceptibility to pulmonary infection, changes in macrophage morphology, and decreased activation of lung natural killer cells, while showing evidence of substantial IL-10 production and accumulation in lung lesions macrophages, but paradoxically this did not influence the course of the chronic disease. In addition, macrophages from the lungs of xid mice also expressed high levels of CD14. These observations suggest that the xid mutation in cellular signalling has much wider effects on the immune system than previously thought.
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PMID:Interleukin-10 production by lung macrophages in CBA xid mutant mice infected with Mycobacterium tuberculosis. 1588 31

alpha1-Antitrypsin (AAT), a major endogenous inhibitor of serine proteases, plays an important role in minimizing proteolytic injury to host tissue at sites of infection and inflammation. There is now increasing evidence that AAT undergoes post-translational modifications to yield by-products with novel biological activity. One such molecule, the C-terminal fragment of AAT, corresponding to residues 359-394 (C-36 peptide) has been reported to stimulate significant pro-inflammatory activity in monocytes and neutrophils in vitro. In this study we showed that C-36 peptide is present in human lung tissue and mimics the effects of lipopolysaccharide (LPS), albeit with lower magnitude, by inducing monocyte cytokine (TNFalpha, IL-1beta) and chemokine (IL-8) release in conjunction with the activation of nuclear factor-kappaB (NF-kappaB). Using receptor blocking antibodies and protein kinase inhibitors, we further demonstrated that C-36, like LPS, utilizes CD14 and Toll-like receptor 4 (TLR4) receptors and enzymes of the mitogen-activated protein kinase (MAPK) signaling pathways to stimulate monocyte TNFalpha release. The specificity of C-36 effects were demonstrated by failure of a shorter peptide (C-20) to elicit biological activity and the failure of C-36 to inhibit CD3/CD28-stimulated IL-2 receptor expression or proliferation in T-cells which lack TLR4 and CD14. We suggest that C-36 mediates its effects though the activation of LPS signaling pathways.
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PMID:C-36 peptide, a degradation product of alpha1-antitrypsin, modulates human monocyte activation through LPS signaling pathways. 1638 23

CD14/toll-like receptor (TLR)-4 complex on monocytes/macrophages can bind lipopolysaccharide (LPS) and transduce the signals intracellularly. An antibacterial drug, ciprofloxacin (CIP), has been reported to modulate the inflammatory and immune responses. In the present study, we examined the effects of CIP on the LPS-induced activation of monocytes isolated from human peripheral blood mononuclear cells (PBMC). CIP suppressed the expression of CD14, TLR-4, intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, and CD40 and the production of tumor necrosis factor (TNF)-alpha induced by LPS in monocytes. CIP induced the production of prostaglandin (PG)E2 and increased intracellular cyclic adenosine monophosphate (cAMP) levels. Cyclooxygenase (COX)-2 inhibitors, NS398 and indomethacin, reversed the effects of CIP on TNF-alpha production and reduced the levels of different surface antigens, whereas a protein kinase A (PKA) inhibitor, H89, did not. Therefore, CIP might regulate the TNF-alpha production induced by LPS by inhibiting the expression of LPS receptor complex, which seems to be mediated by COX-2 but not the cAMP/PKA pathway.
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PMID:The effect of ciprofloxacin on CD14 and toll-like receptor-4 expression on human monocytes. 1655 56

Calcitonin inhibits bone-resorbing activity of osteoclasts. Expression of mRNA of calcitonin receptor (CTR) and its related proteins was examined in human osteoclasts and their progenitors. CD14-positive (CD14 + macrophages) in the monocytes prepared from human peripheral blood cells differentiated into macrophages (CD14 +) presence of macrophage colony-stimulating factor (M-CSF) or into osteoclast-like cells (OCLs) in the presence of M-CSF plus receptor activator of NFkappaB ligand. CD14 macrophages expressed mRNA of CTR-like receptor (CRLR), receptor activity modifying protein (RAMP) 1, RAMP2, and RAMP3, but not CTR. In contrast, OCLs expressed mRNA of CTR but not CRLR or RAMPs. Human OCLs cultured on dentine slices formed actin rings (corresponding to clear zones) and resorption pits on the slices. Calcitonin disrupted actin rings and inhibited the pit-forming activity of OCLs. CTR is known to couple to cAMP-dependent protein kinase (PKA) and protein kinase C (PKC). The effect of calcitonin on actin ring disruption was partially blocked by adding H-7, an inhibitor of both PKA and PKC. Both forskolin, an activator of PKA, and phorbol myristate, an activator of PKC, disrupted actin rings in OCLs. These results suggest that both PKA- and PKC-mediated signals are involved in calcitonin-induced inhibition of human OCL function.
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PMID:Effects of calcitonin on the function of human osteoclast-like cells formed from CD14-positive monocytes. 1753 51

Acute alcohol use is associated with impaired immune responses and decreased proinflammatory cytokine production. Our earlier studies have shown that acute alcohol intake inhibits NF-kappaB DNA binding in an IkappaBalpha-independent manner. We report using human peripheral blood monocytes and Chinese hamster ovary cells transfected with CD14 cells that acute alcohol treatment in vitro exerts NF-kappaB inhibition by disrupting phosphorylation of p65. Immunoprecipitation of p65 and IkappaBalpha revealed that acute alcohol exposure for 1 h decreased NF-kappaB-IkappaBalpha complexes in the cytoplasm. Phosphorylation of p65 at Ser(536) is mediated by IkappaB kinase (IKK)beta and is required for NF-kappaB-dependent cellular responses. We show that acute alcohol treatment decreased LPS-induced IKKalpha and IKKbeta activity resulting in decreased phosphorylation of p65 at Ser(536). Furthermore, nuclear expression of IKKalpha increased after alcohol treatment, which may contribute to inhibition of NF-kappaB. Decreased phosphorylation of nuclear p65 at Ser(276) was likely not due to alcohol-induced inhibition of protein kinase A and mitogen- and stress-activated protein kinase-1 activity. Although decreased IkappaBalpha phosphorylation after acute alcohol treatment was attributable to reduced IKKbeta activity, degradation of IkappaBalpha during alcohol exposure was IKKbeta-independent. Alcohol-induced degradation of IkappaBalpha in the presence of a 26S proteasome inhibitor suggested proteasome-independent IkappaBalpha degradation. Collectively, our studies suggest that acute alcohol exposure modulates IkappaBalpha-independent NF-kappaB activity primarily by affecting phosphorylation of p65. These findings further implicate an important role for IKKbeta in the acute effects of alcohol in immune cells.
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PMID:Acute alcohol exposure exerts anti-inflammatory effects by inhibiting IkappaB kinase activity and p65 phosphorylation in human monocytes. 1754 5


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