Pro-inflammatory cytokine release in keratinocytes is mediated through the MAPK signal-integrating kinases.
The mitogen-activated protein kinases (MAPKs) are known to play a key role in the regulation of cytokine expression in several cell types. MAPK signal-integrating kinase 1 (Mnk1) is a kinase activated through both the stress- and cytokine-activated p38 MAPK pathway and the classical extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. In this study, we demonstrate that in cultured normal human keratinocytes Mnk1 and its downstream target eukaryotic initiation factor 4E (eIF4E) are phosphorylated in a time-dependent manner in response to stimulation with anisomycin or interleukin (IL)-1beta. Both the stimuli are well-recognized activators of the p38 MAPK pathway. Furthermore, we show that the Mnk inhibitor CGP57380 is capable of inhibiting the phosphorylation of eIF4E in keratinocytes, and that the abolishment of eIF4E phosphorylation dramatically decreases the anisomycin-induced protein release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), IL-1beta and IL-6 as well as the IL-1beta-induced protein release of TNF-alpha. Therefore, we propose that Mnk1 might contribute to the expression of pro-inflammatory cytokines found in inflammatory skin diseases.
Kjellerup
Rasmus Boye
RB
Department of Dermatology, Aarhus University Hospital, Aarhus C, Denmark.
Kragballe
Knud
K
Iversen
Lars
L
Johansen
Claus
C
D000814:Aniline Compounds / Q000494:pharmacology; D000841:Anisomycin / Q000494:pharmacology; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000814:Aniline Compounds; C466997:CGP 57380; D016207:Cytokines; D039561:Eukaryotic Initiation Factor-4E; D053583:Interleukin-1beta; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; D014409:Tumor Necrosis Factor-alpha; D000841:Anisomycin; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases