Role of NF-kappaB/RelA and MAPK pathways in keratinocytes in response to sulfur mustard.
Sulfur mustard (SM) is a strong vesicant that has been used as a chemical warfare agent. To understand the molecular mechanisms that underlie the inflammatory skin reaction in response to SM, we analyzed the activation pattern of the NF-kappaB and mitogen-activated protein kinase (MAPK) pathways. Keratinocytes responded with an induction of the canonical NF-kappaB pathway, including activation of IkappaB kinase 2, followed by phosphorylation and degradation of IkappaBalpha and of the transactivating subunit RelA at Ser536. The biphasic NF-kappaB response was strictly dependent on the transactivating subunit RelA, as demonstrated by keratinocytes lacking RelA. Parallel to NF-kappaB activation, we observed an induction of the Raf-1/MEK1/2/ERK1/2/MSK1 and MKK3/6/p38/MSK1 pathways. Although mitogen and stress-activated kinase 1 has been described as a RelA kinase with Ser276 as its target, this site remained unphosphorylated in response to SM. A further MAPK pathway induced by SM was the MKK4/7/JNK1/2 pathway, which resulted in phosphorylation of the transcription factor activating transcription factor-2, but not c-Jun. Our results indicate that SM induces a complex cellular response in keratinocytes, with the activation of three MAPK pathways and the NF-kappaB pathway.
Rebholz
Bernd
B
Department of Dermatology and Allergology, Ludwig-Maximilian-University Munich, Munich, Germany.
Kehe
Kai
K
Ruzicka
Thomas
T
Rupec
Rudolf A
RA
D000818:Animals; D004247:DNA / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009151:Mustard Gas / Q000494:pharmacology*; D016328:NF-kappa B / Q000502:physiology*; D010766:Phosphorylation; D018808:Transcription Factor AP-1 / Q000502:physiology; D051996:Transcription Factor RelA / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016328:NF-kappa B; C498143:RELA protein, human; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D009151:Mustard Gas