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)

In this study we have used a recently developed human hair follicle whole-organ culture system to investigate the effect of IL-1 alpha on hair follicle growth and hair fiber production. In the presence of 10 ng/ml IL-1 alpha, the growth of cultured human hair follicles ceased within 2-4 days, whereas control hair follicles grew for a period of 7-10 days. IL-1 alpha also inhibited hair fiber growth, but with an onset which occurred 3 days later than that of follicle growth inhibition. An IC50 value of approximately 30 pg/ml was obtained for IL-1 alpha inhibition of follicle growth. Incubation of hair follicles with IL-1 alpha resulted in a rapid, transient reduction in the rate of whole-follicle DNA synthesis. 1000-fold molar excess of IL-1 receptor antagonist prevented IL-1-induced follicle growth inhibition, while antagonist alone was without effect. The selective PKC inhibitor, Ro 31-7549, augmented IL-1-induced inhibition of hair follicle growth, but did not itself affect hair follicle growth. These findings indicate that IL-1 alpha exerts a rapid antiproliferative effect on hair follicles, and that inhibition of hair fiber growth is a secondary response. Thus, IL-1 may play a role in the pathophysiology of inflammatory hair loss conditions, such as alopecia areata, through a direct growth-inhibitory effect on hair follicles.
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PMID:IL-1 alpha inhibits human hair follicle growth and hair fiber production in whole-organ cultures. 821 92

3,4-Diacetoxy benzylidene diacetate (ACP) is a prodrug of protocatechualdehyde (PAL). PAL significantly inhibited interleukin-1 (IL-1) production and release in human monocytes in a dose dependent fashion under lipopolysaccharide (LPS) stimulation. ACP showed inhibitory effects on cartilage destruction of the femoral condyles induced by adjuvant arthritis in vivo in a significant and dose dependent fashion. To clarify the mechanism of action of ACP on rat adjuvant arthritis, we investigated the effects of PAL, a metabolite of ACP, on IL-1 production using synovial cell cultures derived from patients with rheumatoid arthritis. PAL significantly inhibited the IL-1 beta production induced by IL-1 alpha or PMA without inhibition of total protein synthesis and cytotoxicity. A protein kinase C (PKC) inhibitor, staurosporine, also suppressed the IL-1 beta production induced by IL-1 alpha or PMA, suggesting that the PKC pathway plays an important role in IL-1 alpha-induced IL-1 beta production. The calcium ionophore A23187 (A23187) potentiated the IL-1 beta production induced by IL-1 alpha. Whereas PAL slightly inhibited under these conditions, it was not statistically significant. These results suggest that PAL has a favourable action on cartilage destruction through the inhibition of IL-1 production induced by the modification of the PKC pathway.
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PMID:Effect of a benzylidene derivative, a novel antirheumatic agent, on IL-1 production. 823 46

Interleukin-1 (IL-1) is known to be a potent stimulator of bone resorption. The effect of IL-1 has been shown to be mediated, at least in part, by IL-1-induced prostaglandin (PG) E2 production in osteoblasts. The intracellular signal transduction mechanism of IL-1 in the PG production, however, is unknown. In the present study using a mouse osteoblastic cell line, MC3T3-E1 (MC), the possible involvement of two representative signal transduction pathways, protein kinase A (PKA) or protein kinase C (PKC)-dependent pathway in the IL-1 alpha stimulated PGE2 production, was investigated. MC produced PGE2 30 min after the IL-1 stimulation. This was inhibited with cycloheximide, suggesting the involvement of de novo protein synthesis. The IL-1-induced PGE2 production was inhibited by H-7 in a dose dependent manner. Since H-7 is known to inhibit PKA as well as PKC, a more specific inhibitor of PKA KT5720 or staurosporin was used to determine the respective role of PKA or PKC in the production of PGE2. KT5720 inhibited the IL-1-induced PGE2 production in MC in a dose dependent fashion. Similarly, staurosporin inhibited the IL-1-induced PGE2 production in MC in a dose dependent manner. The effect of the activity of PKA or PKC on the production of PGE2 was also investigated. A stimulator of PKA, 8-bromoadenosine 3'5'-cyclicmonophosphate (8-Br-cAMP), as well as a stimulator of PKC phorbol 12-myristate 13-acetate (PMA) induced PGE2 production in MC. The effect of these agents on the PGE2 production was additive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Intracellular mechanism of interleukin-1 alpha-induced prostaglandin E2 (PGE2) production in a mouse osteoblast-like cell line and the possible involvement of protein kinase A and protein kinase C]. 828 36

For the optimal growth of clonogenic cells in acute myeloblastic leukemia (AML), several cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 are required in addition to colony-stimulating factor (CSF), which may be produced by blast cells themselves. In the present study, we addressed the potential role of endogenous production of TNF-alpha and/or IL-1 in the in vitro growth of AML clonogenic cells supported by IL-3. Addition of a specific neutralizing antibody against TNF-alpha (anti-TNF-alpha) to the culture significantly reduced the growth-stimulating effect of IL-3 on the cells in 11 of 14 patients. Simultaneous addition of anti-IL-1 alpha and anti-IL-1 beta also partly affected the growth, although to a much lesser extent when compared to the effect observed with anti-TNF-alpha. In 3 patients, the growth-stimulating effect of IL-3 was completely abrogated by anti-TNF-alpha or a combination of all three antibodies. Constitutive TNF-alpha transcript was observed in 5 patients and TNF-alpha protein was present in culture supernatant. Following in vitro culture, a transient but profound increase in c-fos, c-jun, TNF-alpha and IL-1 beta mRNA levels was observed. Anti-TNF-alpha inhibited the accumulation of TNF-alpha transcript, suggesting that membrane-integrated TNF-alpha may be partly responsible for the induction of TNF-alpha mRNA. It seems likely that the accumulation of these genes occurs through a protein kinase C-independent signaling pathway.
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PMID:Growth potentiating activity of endogenous production of interleukin-1 and tumor necrosis factor alpha in blast cells of acute myeloblastic leukemia. 831 77

Rat mucosal keratinocytes serially propagated under permanently serum-free conditions responded to interleukin (IL)-1 beta/IL-alpha and to transforming growth factor (TGF)-alpha/epidermal growth factor (EGF) (as well as to 12-O-tetradecanoylphorbol-13-acetate (TPA)) by upregulation of M(r) 95,000 gelatinase (MMP-9) (M(r) 95K GL) and fibroblast-type collagenase (MMP-1) (FIB-CL), whereas control cells expressed barely detectable levels of either of these enzymes. The cells secreted 8-10 micrograms/10(6) cells/day (M(r) 95K GL) and 2-3 micrograms/10(6) cells/day (FIB-CL) of enzyme protein for at least 24 h when maximally induced. This level was attained only after a 24-h lag period, and the earliest emergence of enzyme protein in the culture medium required 10-14 h. IL-1 beta was by far the most potent cytokine with maximal effect already at 10(-10) M, whereas IL-1 alpha, TGF-alpha, and EGF required 20-100-fold higher concentrations. Pretreatment of the cells with TPA (10(-7) M) abolished the subsequent response to IL-1 beta, TGF-alpha, and EGF and at the same time resulted in > 90% reduction of cytosolic protein kinase C activity. Surprisingly, staurosporine, a potent kinase inhibitor, not only failed to block growth factor/cytokine responses but itself stimulated expression of the enzymes at a magnitude comparable to TPA. The inducing effect of TGF-alpha/EGF was down-regulated by 70-85% by 10(-7) M dexamethasone. Dexamethasone was less effective in ablating the IL-1 beta response yielding 60% reduction M(r) 95K GL and little or no reduction of FIB-CL. Dexamethasone also failed to block the TPA response.
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PMID:Interleukin-1 beta and transforming growth factor-alpha/epidermal growth factor induce expression of M(r) 95,000 type IV collagenase/gelatinase and interstitial fibroblast-type collagenase by rat mucosal keratinocytes. 839 30

Epidermal growth factor is a potential mitogen for many different human tumours. Its effect is mediated via a bispecific receptor (EGFR), the expression of which correlates well with invasive disease. We investigated the modulation of EGFR by cytokines produced following bacillus Calmette Guerin (BCG)-immunotherapy. Our data demonstrate the IFN gamma, TNF alpha and IL-1 alpha can decrease the expression of EGFR on some bladder tumour cell lines. IFN gamma reduced EGFR expression on two of eight cell lines (RT4, SD). However, IL-1 and TNF did not share this activity. When cells were treated with a combination of all three cytokines, EGFR was decreased on three cell lines (RT4, RT112, SD) and furthermore, the change in the receptor expression was even more marked. Treatment with phorbol ester (thereby activating protein kinase C) resulted in rapid disappearance of the receptor from the cell surface. Interestingly, the decrease of EGFR expression did not require protein synthesis. Although the cytokines studied could down modulate EGFR, this only occurred on three out of eight cell lines; therefore, it is unlikely that the suppression of proliferative activity caused by cytokine-induced decrease of EGFR expression is central to the antitumour action of BCG therapy, but in a proportion of tumours this mechanism may be involved.
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PMID:Cytokine modulation of epidermal growth factor receptor expression on bladder cancer cells is not a major contributor to the antitumour activity of cytokines. 856 66

We examined the effects of interleukin-1 alpha (IL-1 alpha) and involvement of protein kinases on prostaglandin production in cultured ovine astroglia. Ovine astroglia were exposed to media alone, or 10 ng/mL IL-1 alpha and prostaglandin F2 alpha (PGF2 alpha) levels were analyzed using enzyme immunoassay. Application of IL-1 alpha augmented the production of PGF2 alpha at 4 h. Coapplication of H-7 (10-1000 microM) and staurosporine (0.1-10 microM), inhibitors of protein kinase C (PKC), blocked IL-1 alpha-induced PGF2 alpha production. IL-1 alpha increased cyclooxygenase (COX) activity while coapplication of staurosporine prevented an increase, implying that COX activity was dependent upon PKC activation. In contrast, forskolin, sodium nitroprusside, and cyclic nucleotide analogs alone did not affect prostaglandin production significantly, excluding the involvement of cAMP/cGMP-dependent protein kinases. Coapplication of quinacrine (10 microM) and bromophenacyl bromide (100 microM), inhibitors of phospholipase A2 (PLA2), prevented the IL-1 alpha-induced increases in PGF2 alpha production. Lastly, IL-1 alpha increased labeled arachidonic acid (AA) release whereas coaddition of quinacrine (10 microM) attenuated increased AA release. Therefore, we propose that IL-1 alpha enhances prostaglandin production by ovine astroglia via steps involving activation of PKC and increased activity of COX and PLA2.
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PMID:Protein kinases and prostaglandin production in ovine astroglia. 858 70

Interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha) induce tissue factor in endothelium, which results in activation of the coagulation cascade. Despite extensive investigation, in which various stimuli that induce tissue factor have been defined, the intracellular processes that control tissue factor expression are not well understood. It has been proposed that protein kinase C regulates tissue factor expression primarily because phorbol myristate acetate, the protein kinase C activator, induces tissue factor expression. In this study we examined whether IL-1 alpha- or TNF-alpha-stimulated tissue factor production is regulated through a protein kinase C-dependent mechanism. Northern blot analysis showed that cytokine-induced tissue factor mRNA was significantly reduced in human umbilical vein endothelial cells treated with calphostin C, a specific protein kinase C inhibitor. Tissue factor functional activity was decreased in the presence of calphostin C as well. Calphostin C also inhibited phorbol myristate acetate-induced tissue factor expression. In contrast, calphostin C did not alter cytokine induction of E-selectin or prostacyclin release. Because calcium stimulates protein kinase C binding to the membrane and its resulting catalytic activity, human umbilical vein endothelial cells were exposed to IL-1 alpha or TNF-alpha in the presence of calcium ionophore A23187. A23187 had little effect alone but significantly augmented cytokine stimulation of tissue factor mRNA. Okadaic acid, a phosphatase inhibitor, increased cytokine-induced tissue factor mRNA compared with cytokine alone, which suggests that a phosphorylation event is important in tissue factor expression. These results indicate that protein kinase C is involved in cytokine activation of endothelial cell tissue factor expression.
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PMID:Protein kinase C regulates cytokine-induced tissue factor transcription and procoagulant activity in human endothelial cells. 859

The protein kinase C (PKC) activator bryostatin 1 (bryo) has substantial antileukemic and hematopoietic actions. Bryo promotes the in vitro growth of normal hematopoietic progenitors by inducing the release of growth factors from accessory cells. We have examined the effects of bryo on the expression and release of certain myeloid growth factors from fibroblastlike marrow stromal cells (MSC). Substantial release of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF). or interleukin-6 (IL-6) following bryo treatment was seen only in MSC cultures contaminated with macrophages. Bryo alone was ineffective in inducing release of the cytokines from MSC cultures containing only fibroblastlike stromal cells. When MSC were treated with IL-1alpha, substantial quantities of the cytokines (G-CSF, GM-CSF,IL-6) were released. Bryo acted synergistically with IL-1 alpha to significantly increase cytokine release to- to nine-fold compared to IL-1alpha alone (p < 0.016). Neither Il-1alpha nor bryo, alone or in combination, induced release of stem cell factor (scf) from MSC. The synergistic interaction between IL-1alpha and bryo was dose- and schedule-dependent, requiring simultaneous application of IL-1alpha and bryo for optimum effect. Bryo alone induced no G-CSF mRNA accumulation but increased the level seen with IL-1alpha treatment by 50%. The synergistic interaction of bryo and IL-1alpha required PKC, since it was antagonized by agents which depleted or inhibited PKC but not by a protein kinase A antagonist. The increase in G-CSF mRNA was associated with a marked increase in mRNA stability. Bryostatin may promote the release of cytokines from several accessory cell populations, including MSC, to accomplish its in vivo hematopoietic effects.
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PMID:Bryostatin 1 acts synergistically with interleukin-1 alpha to induce secretion of G-CSF and other cytokines from marrow stromal cells. 860 66

Immune globulin for intravenous use (IVIG) has been used in many inflammatory conditions due to its immunomodulatory potential. The effector mechanisms are incompletely understood. This study dealt with the effects of IVIG on cytokine production in vitro. Cytokine synthesis was identified at the single-cell level using cytokine-specific MAb and indirect immunocytochemical techniques. Peripheral blood mononuclear cells (PBMC) were stimulated for 96 h by immobilized anti-CD3 MAb or by a combination of a protein kinase C activator (PMA) and a calcium ionophore (ionomycin). The addition of IVIG (6 mg/ml) caused a marked inhibition of proliferation and blast transformation despite unaffected cell survival. Anti-CD3-stimulated cultures containing IVIG exhibited a significant inhibition of production of T-cell derived lymphokines IL-2, IL-10, TNF-beta, IFN-gamma and TNF-alpha (made by both monocytes and T cells), while synthesis of the monokine IL-8 was significantly increased. The expression of IL-2 receptors was significantly suppressed. Similar but transient inhibition of most T-cell products (IL-2, IL-3, IL-4, IL-5, IL-10, TNF-beta and GM-CSF) was noted in the PMA/ionomycin-containing cultures. In contrast, no effects were found on IFN-gamma or TNF-alpha production. The superantigen streptococcal pyrogenic exotoxin-A (SPE-A) induced vigorous cell activation and extensive cytokine synthesis. IVIG was added either at the beginning or 24 h after the initiation of cultures in order to elucidate the importance of direct toxin-neutralization. Addition of IVIG from the beginning of cultures induced a strong reduction of blast transformation and an almost complete inhibition of lymphokine production, in particular of IFN-gamma and TNF-beta. Supplementation with IVIG 24 h after initiation of cultures also led to a significant decrease in lymphokine synthesis. Monokine production (IL-1 alpha, IL-1 beta, IL-1ra, IL-6 and IL-8) was either unaffected or even increased. These two facts argue against direct antigen-neutralization as being the only mechanism at work. However, in IVIG-exposed PBMC stimulated with LPS, IL-6 production was significantly reduced. A significant upregulation of IL-1ra was noticed in unstimulated PBMC cultured with IVIG. The results in all the experiments did not indicate a cytotoxic effect by IVIG on cell survival and the production of certain cytokines were unaffected. Instead, the authors believe that the results suggest a previously little examined functional link where the humoral immune response may have direct immunoregulatory effects on the cellular immune system.
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PMID:Intravenous immune globulin affects cytokine production in T lymphocytes and monocytes/macrophages. 862 37


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