scholarly journals Contrasting effects of the protein kinase C inhibitor, staurosporine, on cytokine and phorbol ester stimulation of fructose 2,6-bisphosphate and prostaglandin E production by fibroblasts in vitro. Comparative studies using interleukin-1α, tumour necrosis factor α, transforming growth factor β, interferon-γ and 12-O-tetradecanoylphorbol 13-acetate

1990 ◽  
Vol 269 (3) ◽  
pp. 573-577 ◽  
Author(s):  
D J Taylor ◽  
J M Evanson ◽  
D E Woolley
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Dermal Fibroblasts ◽  
Tnf Alpha ◽  
Prostaglandin E ◽  
Kinase C ◽  
Protein Kinase C Inhibitor ◽  
Necrosis Factor

It is known that both interleukin-1 alpha (IL-1 alpha) and 12-O-tetradecanoylphorbol 13-acetate (TPA) promote increases in intracellular levels of the glycolytic regulatory metabolite fructose 2,6-bisphosphate [Fru(2,6)P2] and in the production of prostaglandin E (PGE) by subcultured rheumatoid synovial cells (RSC) and human dermal fibroblasts in vitro. We report here that the protein kinase C inhibitor staurosporine enhanced the IL-1 alpha-induced increase in [Fru(2,6)P2] and PGE production by RSC, whereas in similar concentrations (3-30 nM) this inhibitor decreased the TPA-induced stimulation of these parameters. Staurosporine produced a similar enhancement of the response to IL-1 alpha by normal human dermal fibroblasts. The increased PGE production provoked by tumour necrosis factor alpha (TNF alpha) in RSC was also augmented by staurosporine, but, in contrast, the increases in cellular [Fru(2,6)P2] induced by transforming growth factor beta (TGF beta) and interferon-gamma (IFN-gamma) were diminished. Thus the protein kinase C inhibitor staurosporine discriminates not only between the effects produced by IL-1 alpha and TPA, but also between those of IL-1 alpha and two other cytokines (but not between IL-1 alpha and TNF alpha). These findings suggest that IL-1 alpha and probably TNF alpha act via an intracellular mechanism different from that mediating the action of TPA, TGF-beta and IFN-gamma, and provide evidence that staurosporine is capable of amplifying the IL-1 signal.

scholarly journals Downregulation of tumor necrosis factor (TNF) sensitivity via modulation of TNF binding capacity by protein kinase C activators.

1987 ◽  
Vol 166 (6) ◽  
pp. 1788-1797 ◽  
Author(s):  
R Unglaub ◽  
B Maxeiner ◽  
B Thoma ◽  
K Pfizenmaier ◽  
P Scheurich
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Binding Capacity ◽  
Receptor Protein ◽  
Tnf Alpha ◽  
Tnf Receptor ◽  
Kinase C ◽  
Necrosis Factor

The regulatory action of activators for protein kinase C on the specific binding capacity for recombinant human tumor necrosis factor alpha (TNF-alpha) was studied on various human cell lines. Phorbol myristate acetate (PMA) and oleyl acetyl glycerol (OAG) both are able to rapidly downregulate TNF-binding capacity of normal and malignant cells derived from various tissues. As PMA treatment did not enhance internalization of TNF-alpha-receptor complexes at 37 degrees C, and since OAG was able to downregulate TNF-binding capacity under conditions where internalization and shedding of receptor protein are prevented, we conclude that protein kinase C controls ligand affinity of the TNF-receptor protein, possibly via direct phosphorylation. Protein kinase C triggered downregulation of TNF-alpha-binding capacity concomitantly resulted in reduction of TNF-alpha sensitivity, as revealed from decreased cytotoxic action of TNF-alpha on L 929 cells and from inhibition of TNF-alpha-mediated enhancement of HLA class II antigen expression in Colo 205 cells. Restoration of TNF-binding capacity upon abrogation of protein kinase C stimulation leads to full recovery of TNF responsiveness, further supporting the close linkage of TNF-receptor expression and TNF sensitivity. These data suggest that regulation of TNF-binding capacity by protein kinase C is one of the cellular control mechanisms of TNF responsiveness.

scholarly journals Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1110
Author(s):  
Blerina Shkodra ◽  
Adrian T. Press ◽  
Antje Vollrath ◽  
Ivo Nischang ◽  
Stephanie Schubert ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Targeted Delivery ◽  
Near Infrared ◽  
Water Solubility ◽  
Analytical Ultracentrifugation ◽  
Therapeutic Potential ◽  
Kinase C ◽  
Protein Kinase C Inhibitor

Bisindolylmaleimide I (BIM-I) is a competitive pan protein kinase C inhibitor with anti-inflammatory and anti-metastatic properties, suggested to treat inflammatory diseases and various cancer entities. However, despite its therapeutic potential, BIM-I has two major drawbacks, i.e., it has a poor water solubility, and it binds the human ether-à-go-go-related gene (hERG) ion channels, potentially causing deadly arrhythmias. In this case, a targeted delivery of BIM-I is imperative to minimize peripheral side effects. To circumvent these drawbacks BIM-I was encapsulated into nanoparticles prepared from poly(lactic-co-glycolic acid) (PLGA) functionalized by the near-infrared dye DY-635. DY-635 served as an active targeting moiety since it selectively binds the OATP1B1 and OATP1B3 transporters that are highly expressed in liver and cancer cells. PLGA-DY-635 (BIM-I) nanoparticles were produced by nanoprecipitation and characterized using dynamic light scattering, analytical ultracentrifugation, and cryogenic transmission electron microscopy. Particle sizes were found to be in the range of 20 to 70 nm, while a difference in sizes between the drug-loaded and unloaded particles was observed by all analytical techniques. In vitro studies demonstrated that PLGA-DY-635 (BIM-I) NPs prevent the PKC activation efficiently, proving the efficacy of the inhibitor after its encapsulation, and suggesting that BIM-I is released from the PLGA-NPs. Ultimately, our results present a feasible formulation strategy that improved the cytotoxicity profile of BIM-I and showed a high cellular uptake in the liver as demonstrated in vivo by intravital microscopy investigations.

scholarly journals Evidence that interleukin-1 and phorbol esters activate NF-kappa B by different pathways: role of protein kinase C.

1991 ◽  
Vol 2 (4) ◽  
pp. 329-335 ◽  
Author(s):  
K Bomsztyk ◽  
J W Rooney ◽  
T Iwasaki ◽  
N A Rachie ◽  
S K Dower ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Line ◽  
Phorbol Esters ◽  
Interleukin 1 ◽  
Interleukin 2 ◽  
Nf Kappa B ◽  
Kinase C ◽  
Protein Kinase C Inhibitor

Nuclear factor kappa B (NF-kappa B) is a ubiquitous transcription factor that affects expression of many genes, including immunoglobulin kappa (kappa), the interleukin-2 receptor alpha chain, and two genes in HIV-1. NF-kappa B can be activated by a number of stimuli, including pharmacological stimulation of protein kinase C by phorbol 12-myristate 13-acetate (PMA) and treatment in vitro with either protein kinase C or protein kinase A. This has lead to the proposal that these kinases are key enzymes in the physiological activation of NF-kappa B as well. We have used a murine B cell line, 70Z/3, and T cell line, EL-4 6.1 C10, to study the activation of NF-kappa B by two physiological activators, interleukin-1 alpha (IL-1) and lipopolysaccharide (LPS). There are four reasons to propose that these agents activate pathways that do not include protein kinase C as a major component in these cell lines. First, the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) strongly inhibited PMA-induced activation of NF-kappa B in 70Z/3 cells but had no effect on NF-kappa B activated by IL-1 or LPS. Second, depletion of protein kinase C by prolonged growth of 70Z/3 in PMA abrogated the capacity of the cells to activate NF-kappa B in response to further PMA treatment. However, these same cells activated NF-kappa B normally after either IL-1 or LPS treatment. Third, IL-1 effectively activated NF-kappa B in EL-4 6.1 C10 cells, but PMA did not. Fourth, interferon-gamma is a potent activator of protein kinase C in 70Z/3 cells, but is completely inactive in the mobilization of NF-kappa B. These results suggest that the physiological inducers IL-1 and LPS activate NF-kappa B by pathways independent of protein kinase C in both 70Z/3 and EL-4 6.1 C10 cells.

scholarly journals Protein kinase C-dependent phosphorylation is involved in resistance to tumour necrosis factor-α-induced cytotoxicity in a human monocytoid cell line

1993 ◽  
Vol 292 (1) ◽  
pp. 289-294 ◽  
Author(s):  
L E Sampson ◽  
A Mire-Sluis ◽  
A Meager
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Phosphorylation ◽  
Cell Line ◽  
Tumour Necrosis ◽  
Tnf Alpha ◽  
Protective Mechanisms ◽  
Kinase C ◽  
Pkc Inhibitors ◽  
Necrosis Factor

To investigate the mechanism underlying resistance to tumour necrosis factor-alpha (TNF alpha)-induced cytotoxicity, we have developed a human hybrid cell line, designated A10, derived from the fusion of human U-937 monocytoid cells and human monocytes, which expressed large numbers of TNF alpha receptors and yet remained highly resistant to TNF alpha. However, in the presence of the protein kinase C (PKC) inhibitors RO-31-7549 or RO-31-8220 (donated by Roche), these cells became sensitive to TNF alpha-induced cytotoxicity, suggesting that PKC activity is required for protective mechanisms. On investigation of protein phosphorylation in TNF alpha-stimulated permeabilized A10 cells, a rapid increase in serine/threonine phosphorylation of phosphoproteins of molecular masses 130, 90, 80, 65 and 42 kDa was found. Subsequently, we found a similar pattern of increased phosphorylation following stimulation of A10 cells with mezerein, a phorbol ester derivative which activates PKC, a serine/threonine kinase. The theory that activation of PKC was responsible for increased phosphorylation was confirmed by a dose-dependent inhibition of the TNF alpha-induced protein phosphorylation by the PKC inhibitors RO-31-7549 and RO-31-8220. The possible link between the TNF alpha-stimulated early protein phosphorylation events and the maintenance of protective mechanisms against TNF alpha-induced cytotoxicity is discussed.

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