title: Protein expression of TNF-alpha in psoriatic skin is regulated at a posttranscriptional level by MAPK-activated protein kinase 2.
abstract: Alterations in specific signal transduction pathways may explain the increased expression of proinflammatory cytokines seen in inflammatory diseases such as psoriasis. We reveal increased TNF-alpha protein expression, but similar TNF-alpha mRNA levels, in lesional compared with nonlesional psoriatic skin, demonstrating for the first time that TNF-alpha expression in lesional psoriatic skin is regulated posttranscriptionally. Increased levels of activated MAPK-activated protein kinase 2 (MK2) together with increased MK2 kinase activity were found in lesional compared with nonlesional psoriatic skin. Immunohistochemical analysis showed that activated MK2 was located in the basal layers of the psoriatic epidermis, whereas no positive staining was seen in nonlesional psoriatic skin. In vitro experiments demonstrated that both anisomycin and IL-1beta caused a significant activation of p38 MAPK and MK2 in cultured normal human keratinocytes. In addition, TNF-alpha protein levels were significantly up-regulated in keratinocytes stimulated with anisomycin or IL-1beta. This increase in TNF-alpha protein expression was completely blocked by the p38 inhibitor, SB202190. Transfection of cultured keratinocytes with MK2-specific small interfering RNA led to a significant decrease in MK2 expression and a subsequent significant reduction in the protein expression of the proinflammatory cytokines TNF-alpha, IL-6, and IL-8, whereas no change in the expression of the anti-inflammatory cytokine IL-10 was seen. This is the first time that MK2 expression and activity have been investigated in an inflammatory disease such as psoriasis. The results strongly suggest that increased activation of MK2 is responsible for the elevated and posttranscriptionally regulated TNF-alpha protein expression in psoriatic skin, making MK2 a potential target in the treatment of psoriasis.
authors.affiliation: Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark. clausoglotte@hotmail.com
authors.forename: Claus
authors.initials: C
authors.lastname: Johansen
authors.forename: Anne Toftegaard
authors.initials: AT
authors.lastname: Funding
authors.forename: Kristian
authors.initials: K
authors.lastname: Otkjaer
authors.forename: Knud
authors.initials: K
authors.lastname: Kragballe
authors.forename: Uffe Birk
authors.initials: UB
authors.lastname: Jensen
authors.forename: Mogens
authors.initials: M
authors.lastname: Madsen
authors.forename: Lise
authors.initials: L
authors.lastname: Binderup
authors.forename: Tine
authors.initials: T
authors.lastname: Skak-Nielsen
authors.forename: Marianne Scheel
authors.initials: MS
authors.lastname: Fjording
authors.forename: Lars
authors.initials: L
authors.lastname: Iversen
mesh_terms: D000328:Adult; D000841:Anisomycin / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005455:Fluorescent Antibody Technique; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D011494:Protein Kinases / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011565:Psoriasis / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012867:Skin / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000841:Anisomycin; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D047908:Intracellular Signaling Peptides and Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2