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Your search keyword '"Dillman JF"' showing total 2 results
Start Over Author "Dillman JF" Journal toxicology in vitro an international journal published in association with bibra
2 results on '"Dillman JF"'

1. Cytokine regulation by MAPK activated kinase 2 in keratinocytes exposed to sulfur mustard.

Author

Yego EC and Dillman JF 3rd

Subjects
Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cells, Cultured, Chemical Warfare Agents chemistry, Cytokines chemistry, Cytokines genetics, Dermatologic Agents antagonists & inhibitors, Humans, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Irritants antagonists & inhibitors, Irritants toxicity, Keratinocytes cytology, Keratinocytes immunology, Keratinocytes metabolism, Kinetics, Mustard Gas chemistry, Phosphorylation drug effects, Protein Kinase Inhibitors pharmacology, Protein Processing, Post-Translational drug effects, Protein Serine-Threonine Kinases antagonists & inhibitors, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, RNA Interference, RNA, Messenger metabolism, RNA, Small Interfering, Up-Regulation drug effects, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors, p38 Mitogen-Activated Protein Kinases chemistry, p38 Mitogen-Activated Protein Kinases genetics, p38 Mitogen-Activated Protein Kinases metabolism, Chemical Warfare Agents toxicity, Cytokines metabolism, Dermatologic Agents toxicity, Intracellular Signaling Peptides and Proteins agonists, Keratinocytes drug effects, MAP Kinase Signaling System drug effects, Mustard Gas toxicity
Abstract

Uncontrolled inflammation contributes to cutaneous damage following exposure to the warfare agent bis(2-chloroethyl) sulfide (sulfur mustard, SM). Activation of the p38 mitogen activated protein kinase (MAPK) precedes SM-induced cytokine secretion in normal human epidermal keratinocytes (NHEKs). This study examined the role of p38-regulated MAPK activated kinase 2 (MK2) during this process. Time course analysis studies using NHEK cells exposed to 200μM SM demonstrated rapid MK2 activation via phosphorylation that occurred within 15 min. p38 activation was necessary for MK2 phosphorylation as determined by studies using the p38 inhibitor SB203580. To compare the role of p38 and MK2 during SM-induced cytokine secretion, small interfering RNA (siRNA) targeting these proteins was utilized. TNF-α, IL-1β, IL-6 and IL-8 secretion was evaluated 24h postexposure, while mRNA changes were quantified after 8h. TNF-α, IL-6 and IL-8 up regulation at the protein and mRNA level was observed following SM exposure. IL-1β secretion was also elevated despite unchanged mRNA levels. p38 knockdown reduced SM-induced secretion of all the cytokines examined, whereas significant reduction in SM-induced cytokine secretion was only observed with TNF-α and IL-6 following MK2 knockdown. Our observations demonstrate potential activation of other p38 targets in addition to MK2 during SM-induced cytokine secretion., (Copyright © 2013. Published by Elsevier Ltd.)

Published
2013
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2. An inhibitor of p38 MAP kinase downregulates cytokine release induced by sulfur mustard exposure in human epidermal keratinocytes.

Author

Dillman JF 3rd, McGary KL, and Schlager JJ

Subjects
Cells, Cultured, Culture Media, Conditioned chemistry, Dose-Response Relationship, Drug, Down-Regulation, Drug Combinations, Enzyme Inhibitors pharmacology, Humans, Imidazoles pharmacology, Keratinocytes metabolism, Phosphorylation, Pyridines pharmacology, p38 Mitogen-Activated Protein Kinases biosynthesis, Chemical Warfare Agents toxicity, Cytokines metabolism, Keratinocytes drug effects, Mustard Gas toxicity, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
Abstract

Sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) is a potent alkylating agent that induces skin vessication after cutaneous exposure. Previous work has revealed that SM induces the production of inflammatory cytokines, including IL-8, IL-6, TNF-alpha, and IL-1beta, in keratinocytes. The p38 MAP kinase (MAPK14) signaling pathway is activated via phosphorylation in response to cellular stress and has been implicated in the upregulation of cytokines in response to stress. We investigated the role of p38 MAP kinase in inflammatory cytokine upregulation following SM exposure. A dose response study in cultured human epidermal keratinocytes (HEK) revealed increasing phosphorylation of p38 MAP kinase in response to increasing concentrations of SM. A time course at the 200 microM exposure revealed that p38 MAP kinase phosphorylation is induced by 15 min post-exposure, peaks at 30 min and is sustained at peak levels until 8 h post-exposure. Phosphorylation of the upstream kinase MKK3/6 was also detected. Assay of the SM-exposed HEK culture media for cytokines revealed that exposure to 200 microM SM increased IL-8, IL-6, TNF-alpha, and IL-1beta. When cells exposed to 200 microM SM were treated with the p38 MAP kinase inhibitor SB203580, the levels of IL-8, IL-6, and TNF-alpha and IL-1beta were significantly decreased when compared with cells that were untreated. These results show that p38 MAP kinase plays a role in SM-induced cytokine production in HEK and suggest that inhibiting this pathway may alleviate the profound inflammatory response elicited by cutaneous SM exposure.

Published
2004
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