scholarly journals A Case of Non-Resolving MEK Inhibitor-Associated Retinopathy

2019 ◽  
Vol 10 (3) ◽  
pp. 334-338
Author(s):  
John R. Chancellor ◽  
David A. Kilgore ◽  
Ahmed B. Sallam ◽  
Richard C. Allen ◽  
Sami H. Uwaydat
Keyword(s):  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Drug Discontinuation ◽  
Serous Fluid ◽  
Factor Inhibitor ◽  
Mitogen Activated Protein ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Kinase Pathway ◽  
Stimulating Factor

The mitogen-activated kinase pathway plays an important role in cell survival, and its dysregulation is associated with cancers such as melanoma. Drugs designed to target this pathway have been associated with serous retinal detachments in a new entity termed MEK inhibitor-associated retinopathy (MEKAR). MEKAR has classically been described as self-limiting, with serous fluid often resolving without discontinuation of the drug. We present a case in which a patient undergoing treatment for metastatic melanoma with lacnotuzumab, a macrophage colony-stimulating factor inhibitor that blocks an upstream component of the mitogen-activated protein kinase pathway, developed serous retinopathy that did not resolve despite drug discontinuation.

Cytokine-Specific Activation of Distinct Mitogen-Activated Protein Kinase Subtype Cascades in Human Neutrophils Stimulated by Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, and Tumor Necrosis Factor-

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 341-349 ◽  
Author(s):  
Kenichi Suzuki ◽  
Masayuki Hino ◽  
Fumihiko Hato ◽  
Noriyuki Tatsumi ◽  
Seiichi Kitagawa
Keyword(s):  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Human Neutrophils ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Mitogen Activated Protein ◽  
Upstream Kinase ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract To clarify the differences of the signaling pathways used by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor- (TNF), we investigated activation of mitogen-activated protein kinase (MAPK) subtype cascades in human neutrophils stimulated by these cytokines. G-CSF exclusively tyrosine-phosphorylated extracellular signal-regulated kinase (ERK). GM-CSF tyrosine-phosphorylated ERK strongly and p38 MAPK weakly, whereas TNF tyrosine-phosphorylated p38 MAPK strongly and ERK weakly. Consistent with these findings, MEK, an upstream kinase of ERK, was phosphorylated by G-CSF, GM-CSF, and TNF, whereas MKK3/MKK6, an upstream kinase of p38 MAPK, was phosphorylated by GM-CSF and TNF, but not by G-CSF. The potency of these cytokines to phosphorylate ERK and MEK was GM-CSF > G-CSF > TNF, whereas that to phosphorylate p38 MAPK and MKK3/MKK6 was TNF > GM-CSF. C-Jun amino-terminal kinase (JNK) was not tyrosine-phosphorylated by any cytokine despite the existence of JNK proteins in human neutrophils, whereas it was tyrosine-phosphorylated by TNF in undifferentiated and all-trans retinoic acid-differentiated HL-60 cells. Increased phosphorylation of ERK or p38 MAPK was detected within 1 to 5 minutes after stimulation with each cytokine and was dependent on the concentrations of cytokines used. MEK inhibitor (PD98059) reduced tyrosine phosphorylation of ERK, but not p38 MAPK, induced by G-CSF, GM-CSF, or TNF. GM-CSF– or TNF-induced superoxide (O2−) release was inhibited by p38 MAPK inhibitor (SB203580) in a dose-dependent manner, suggesting the possible involvement of p38 MAPK in GM-CSF– or TNF-induced O2− release. The results indicate that G-CSF, GM-CSF, and TNF activate the overlapping but distinct MAPK subtype cascades in human neutrophils and suggest that the differential activation of ERK and p38 MAPK cascades may explain the differences of the effects of these cytokines on human neutrophil functions.

Cytokine-Specific Activation of Distinct Mitogen-Activated Protein Kinase Subtype Cascades in Human Neutrophils Stimulated by Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, and Tumor Necrosis Factor-

Blood ◽  
1999 ◽  
Vol 93 (1) ◽  
pp. 341-349 ◽  
Author(s):  
Kenichi Suzuki ◽  
Masayuki Hino ◽  
Fumihiko Hato ◽  
Noriyuki Tatsumi ◽  
Seiichi Kitagawa
Keyword(s):  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Human Neutrophils ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Mitogen Activated Protein ◽  
Upstream Kinase ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

To clarify the differences of the signaling pathways used by granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor- (TNF), we investigated activation of mitogen-activated protein kinase (MAPK) subtype cascades in human neutrophils stimulated by these cytokines. G-CSF exclusively tyrosine-phosphorylated extracellular signal-regulated kinase (ERK). GM-CSF tyrosine-phosphorylated ERK strongly and p38 MAPK weakly, whereas TNF tyrosine-phosphorylated p38 MAPK strongly and ERK weakly. Consistent with these findings, MEK, an upstream kinase of ERK, was phosphorylated by G-CSF, GM-CSF, and TNF, whereas MKK3/MKK6, an upstream kinase of p38 MAPK, was phosphorylated by GM-CSF and TNF, but not by G-CSF. The potency of these cytokines to phosphorylate ERK and MEK was GM-CSF > G-CSF > TNF, whereas that to phosphorylate p38 MAPK and MKK3/MKK6 was TNF > GM-CSF. C-Jun amino-terminal kinase (JNK) was not tyrosine-phosphorylated by any cytokine despite the existence of JNK proteins in human neutrophils, whereas it was tyrosine-phosphorylated by TNF in undifferentiated and all-trans retinoic acid-differentiated HL-60 cells. Increased phosphorylation of ERK or p38 MAPK was detected within 1 to 5 minutes after stimulation with each cytokine and was dependent on the concentrations of cytokines used. MEK inhibitor (PD98059) reduced tyrosine phosphorylation of ERK, but not p38 MAPK, induced by G-CSF, GM-CSF, or TNF. GM-CSF– or TNF-induced superoxide (O2−) release was inhibited by p38 MAPK inhibitor (SB203580) in a dose-dependent manner, suggesting the possible involvement of p38 MAPK in GM-CSF– or TNF-induced O2− release. The results indicate that G-CSF, GM-CSF, and TNF activate the overlapping but distinct MAPK subtype cascades in human neutrophils and suggest that the differential activation of ERK and p38 MAPK cascades may explain the differences of the effects of these cytokines on human neutrophil functions.

scholarly journals Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 2033-2043 ◽  
Author(s):  
Stephen R. Clark ◽  
Christopher J. Guy ◽  
Martin J. Scurr ◽  
Philip R Taylor ◽  
Ann P. Kift-Morgan ◽  
...  
Keyword(s):  
Staphylococcus Epidermidis ◽  
Mitogen Activated Protein Kinase ◽  
Human Neutrophils ◽  
Extracellular Signal Regulated Kinase ◽  
Bacterial Peritonitis ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract5-Lipoxygenase (5-LOX) plays key roles in infection and allergic responses. Herein, four 5-LOX–derived lipids comprising 5-hydroxyeicosatetraenoic acid (HETE) attached to phospholipids (PLs), either phosphatidylethanolamine (PE) or phosphatidylcholine (18:0p/5-HETE-PE, 18:1p/5-HETE-PE, 16:0p/5-HETE-PE, and 16:0a/5-HETE-PC), were identified in primary human neutrophils. They formed within 2 minutes in response to serum-opsonized Staphylococcus epidermidis or f-methionine-leucine-phenylalanine, with priming by lipopolysaccharide, granulocyte macrophage colony-stimulating factor, or cytochalasin D. Levels generated were similar to free 5-HETE (0.37 ± 0.14 ng vs 0.55 ± 0.18 ng/106 cells, esterified vs free 5-HETE, respectively). They remained cell associated, localizing to nuclear and extranuclear membrane, and were formed by fast esterification of newly synthesized free 5-HETE. Generation also required Ca2+, phospholipase C, cytosolic and secretory phospholipase A2, 5-LOX activating protein, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1. 5-HETE-PLs were detected in murine S epidermidis peritonitis, paralleling neutrophil influx, and in effluent from Gram-positive human bacterial peritonitis. Formation of neutrophil extracellular traps was significantly enhanced by 5-LOX inhibition but attenuated by HETE-PE, whereas 5-HETE-PE enhanced superoxide and interleukin-8 generation. Thus, new molecular species of oxidized PL formed by human neutrophils during bacterial infection are identified and characterized.

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