title: Sulfur mustard induces differentiation in human primary keratinocytes: opposite roles of p38 and ERK1/2 MAPK.
abstract: The chemical warfare agent sulfur mustard (SM) severely affects the regeneration capacity of skin. The underlying molecular and cellular mechanisms, however, are far from clear. Here, we demonstrate that normal human epidermal keratinocytes (NHEK) after exposure to SM strongly upregulated expression of keratin-1, involucrin, and loricrin, thus indicating premature epidermal differentiation. Furthermore, proliferation was repressed after treatment with SM. Analysis of intracellular signaling in NHEK revealed that SM enhances phosphorylation, nuclear translocation, and activity of the mitogen-activated protein kinases (MAPK) p38 and ERK1/2. Inhibition of p38 activity downregulated expression of keratin-1 and loricrin, whereas blockage of ERK1/2 significantly stimulated biosynthesis of these markers, pointing to opposite roles of p38 and ERK1/2 in the differentiation process. Simultaneous interruption of p38 and ERK1/2 activity led to a decreased expression of keratin-1 and loricrin. This suggests that NHEK differentiation is essentially controlled by p38 activity which may be negatively influenced by ERK1/2 activity. Functional analysis demonstrated that SM affects NHEK in their ability to migrate through extracellular matrix which can be rescued upon application of an inhibitor of p38 activity. Thus, our findings indicate that SM triggers premature differentiation in keratinocytes via p38 activity which may contribute to impaired regeneration of SM-injured skin.
authors.affiliation: Division of Clinical Chemistry and Clinical Biochemistry, Ludwig-Maximilians-University of Munich, Nussbaumstrasse 20, 80336 Munich, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Popp
authors.forename: Virginia
authors.initials: V
authors.lastname: Egea
authors.forename: Kai
authors.initials: K
authors.lastname: Kehe
authors.forename: Dirk
authors.initials: D
authors.lastname: Steinritz
authors.forename: Annette
authors.initials: A
authors.lastname: Schmidt
authors.forename: Marianne
authors.initials: M
authors.lastname: Jochum
authors.forename: Christian
authors.initials: C
authors.lastname: Ries
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D053556:Keratin-1 / Q000096:biosynthesis; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis; D018613:Microscopy, Confocal; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism* / Q000502:physiology; D009151:Mustard Gas / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology
chemical_list: D053556:Keratin-1; D008565:Membrane Proteins; C064554:loricrin; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D009151:Mustard Gas