Rottlerin, a PKC isozyme-selective inhibitor, affects signaling events and cytokine production in human monocytes

Kontny, Ewa; Kurowska, Weronika; Szczepańska, Katarzyna; Maśliński, Włodzimierz

doi:10.1002/jlb.67.2.249

Cited by 97 publications

(81 citation statements)

References 46 publications

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“…Rottlerin has an inhibitory effect against the PKC delta isoenzyme and can directly regulate several biological phenomena, such as cytokine production, cell adhesion/aggregation, and cell apoptosis. For example, Rottlerin strongly affects the response of human V gamma 9V delta 2 T cells to phosphate antigens (4), CD98-dependent homotypic aggregation (3), the down-regulation of apoptosis (27), TNF-α production (17), the shedding of IL-6 receptor alpha (IL-6Rα) (40), and the modulation of the apoptosis pathway (41). In addition, our studies revealed that nPKC controlled by Rottlerin directly affected the regulation of CD93 expression.…”

Section: Discussionmentioning

confidence: 99%

Regulation of CD93 Cell Surface Expression by Protein Kinase C Isoenzymes

Ikewaki

Kulski

Inoko

2006

Microbiology and Immunology

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Human CD93, also known as complement protein 1, q subcomponent, receptor (C1qRp), is selectively expressed by cells with a myeloid lineage, endothelial cells, platelets, and microglia and was originally reported to be involved in the complement protein 1, q subcomponent (C1q)‐mediated enhancement of phagocytosis. The intracellular molecular events responsible for the regulation of its expression on the cell surface, however, have not been determined. In this study, the effect of protein kinases in the regulation of CD93 expression on the cell surface of a human monocyte‐like cell line (U937), a human NK‐like cell line (KHYG‐1), and a human umbilical vein endothelial cell line (HUV‐EC‐C) was investigated using four types of protein kinase inhibitors, the classical protein kinase C (cPKC) inhibitor Go6976, the novel PKC (nPKC) inhibitor Rottlerin, the protein kinase A (PKA) inhibitor H‐89 and the protein tyrosine kinase (PTK) inhibitor herbimycin A at their optimum concentrations for 24 hr. CD93 expression was analyzed using flow cytometry and glutaraldehyde‐fixed cellular enzyme‐linked immunoassay (EIA) techniques utilizing a CD93 monoclonal antibody (mAb), mNI‐11, that was originally established in our laboratory as a CD93 detection probe. The nPKC inhibitor Rottlerin strongly down‐regulated CD93 expression on the U937 cells in a dose‐dependent manner, whereas the other inhibitors had little or no effect. CD93 expression was down‐regulated by Go6976, but not by Rottlerin, in the KHYG‐1 cells and by both Rottlerin and Go6976 in the HUV‐EC‐C cells. The PKC stimulator, phorbol myristate acetate (PMA), strongly up‐regulated CD93 expression on the cell surface of all three cell‐lines and induced interleukin‐8 (IL‐8) production by the U937 cells and interferon‐γ (IFN‐γ) production by the KHYG‐1 cells. In addition, both Go6976 and Rottlerin inhibited the up‐regulation of CD93 expression induced by PMA and IL‐8 or IFN‐γ production in the respective cell‐lines. Whereas recombinant tumor necrosis factor‐α (rTNF‐α) slightly up‐regulated CD93 expression on the U937 cells, recombinant interleukin‐1β (rIL‐1β), recombinant interleukin‐2 (rIL‐2), recombinant interferon‐γ (rIFN‐γ) and lipopolysaccharide (LPS) had no effect. Taken together, these findings indicate that the regulation of CD93 expression on these cells involves the PKC isoenzymes.

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Section: Discussionmentioning

confidence: 99%

Regulation of CD93 Cell Surface Expression by Protein Kinase C Isoenzymes

Ikewaki

Kulski

Inoko

2006

Microbiology and Immunology

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“…Infection of macrophages with M. avium leads to the activation of PKC, and PKC in turn is involved in the activation of many genes, such as TNF-␣, IL-1, and IL-6 (27,28). PKC functions by regulating the activation of transcription factors such as NF-B, c-Fos, and c-Jun (29 -31).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Toll-Like Receptor 2 Expression by Macrophages FollowingMycobacterium aviumInfection

Wang¹,

Lafuse

Zwilling

2000

The Journal of Immunology

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Recent studies have implicated Toll-like receptors (TLR), especially TLR2 and TLR4, as sentinel receptors that signal the interaction of macrophages with bacterial pathogens via a NF-κB-mediated pathway. The regulation of TLR gene expression, however, has not been intensively studied. Here, we report that TLR2 mRNA was induced following infection of murine macrophages with Mycobacterium avium. The changes in TLR2 mRNA correlated with an increase in TLR2 surface expression. Infection with M. avium resulted in a concomitant decrease in TLR4 mRNA. The effect of M. avium infection on TLR2 mRNA appeared to be mediated, in part, by TLR2 because the induction of the mRNA was partially blocked by preincubation of the macrophages with an anti-human TLR2 Ab. In contrast, the effect of LPS stimulation was mediated via TLR4 because infection of macrophages from LPSd mice, which do not express active TLR4, resulted in an increase in TLR2 mRNA, while treatment of macrophages from these mice with LPS failed to induce TLR2 mRNA. Several cytokines, including TNF-α, IL-1α, and GM-CSF, but not IFN-γ, induced TLR2 mRNA. M. avium infection resulted in the induction of TLR2 mRNA by macrophages from both TNFRI knockout and NF-κB p50 knockout mice.

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“…In addition, since ERK1/2 activation is required for PMA-dependent monocyte differentiation as shown by us here with MEK inhibition studies and by others (33), we conclude that PKC␦ is the critical PKC responsible for PMA-induced monocyte differentiation in U937 cells and that its autophosphorylation on serine 660 probably controls this process. Furthermore, from the 32D cell studies sited above, PKC␦ would be expected to play an important role, generally, in the phorbol ester activation pathway (43) in monocytes.…”

Section: Fig 2 Pma-dependent Activation Of Erk1/2 Is Regulated By Cmentioning

confidence: 99%

CD45 Negatively Regulates Monocytic Cell Differentiation by Inhibiting Phorbol 12-Myristate 13-Acetate-dependent Activation and Tyrosine Phosphorylation of Protein Kinase Cδ

Deszo¹,

Brake²,

Cengel³

et al. 2001

Journal of Biological Chemistry

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The protein-tyrosine phosphatase CD45 is expressed on all monocytic cells, but its function in these cells is not well defined. Here we report that CD45 negatively regulates monocyte differentiation by inhibiting phorbol 12-myristate 13-acetate (PMA)-dependent activation of protein kinase C (PKC) ␦. We found that antisense reduction of CD45 in U937 monocytic cells (CD45as cells) increased by 100% the ability of PMA to enlarge cell size, increase cell cytoplasmic process width and length, and induce surface expression of CD11b. In addition, reduction in CD45 expression caused the duration of peak PMA-induced MEK and extracellular signal-regulated kinase (ERK) 1/2 activity to increase from 5 min to 30 min while leading to a 4-fold increase in PMA-dependent PKC␦ activation. Importantly, PMA-dependent tyrosine phosphorylation of PKC␦ was also increased 4-fold in CD45as cells. Finally, inhibitors of MEK (PD98059) and PKC␦ (rottlerin) completely blocked PMA-induced monocytic cell differentiation. Taken together, these data indicate that CD45 inhibits PMA-dependent PKC␦ activation by impeding PMA-dependent PKC␦ tyrosine phosphorylation. Furthermore, this blunting of PKC␦ activation leads to an inhibition of PKC␦-dependent activation of ERK1/2 and ERK1/2-dependent monocyte differentiation. These findings suggest that CD45 is a critical regulator of monocytic cell development.

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Rottlerin, a PKC isozyme-selective inhibitor, affects signaling events and cytokine production in human monocytes

Cited by 97 publications

References 46 publications

Regulation of CD93 Cell Surface Expression by Protein Kinase C Isoenzymes

Regulation of CD93 Cell Surface Expression by Protein Kinase C Isoenzymes

Regulation of Toll-Like Receptor 2 Expression by Macrophages FollowingMycobacterium aviumInfection

CD45 Negatively Regulates Monocytic Cell Differentiation by Inhibiting Phorbol 12-Myristate 13-Acetate-dependent Activation and Tyrosine Phosphorylation of Protein Kinase Cδ

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