The p38 MAPK regulates IL-24 expression by stabilization of the 3' UTR of IL-24 mRNA.
BACKGROUND
IL-24 (melanoma differentiation-associated gene-7 (mda-7)), a member of the IL-10 cytokine family, possesses the properties of a classical cytokine as well as tumor suppressor effects. The exact role of IL-24 in the immune system has not been defined but studies have indicated a role for IL-24 in inflammatory conditions such as psoriasis. The tumor suppressor effects of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis. Current knowledge on the regulation of IL-24 expression is sparse. Previous studies have suggested that mRNA stabilization is of major importance to IL-24 expression. Yet, the mechanisms responsible for the regulation of IL-24 mRNA stability remain unidentified. As p38 MAPK is known to regulate gene expression by interfering with mRNA degradation we examined the role of p38 MAPK in the regulation of IL-24 gene expression in cultured normal human keratinocytes.


RESULTS
In the present study we show that anisomycin- and IL-1beta- induced IL-24 expression is strongly dependent on p38 MAPK activation. Studies of IL-24 mRNA stability in anisomycin-treated keratinocytes reveal that the p38 MAPK inhibitor SB 202190 accelerates IL-24 mRNA decay suggesting p38 MAPK to regulate IL-24 expression by mRNA-stabilizing mechanisms. The insertion of the 3' untranslated region (UTR) of IL-24 mRNA in a tet-off reporter construct induces degradation of the reporter mRNA. The observed mRNA degradation is markedly reduced when a constitutively active mutant of MAPK kinase 6 (MKK6), which selectively activates p38 MAPK, is co-expressed.


CONCLUSIONS
Taken together, we here report p38 MAPK as a regulator of IL-24 expression and determine interference with destabilization mediated by the 3' UTR of IL-24 mRNA as mode of action. As discussed in the present work these findings have important implications for our understanding of IL-24 as a tumor suppressor protein as well as an immune modulating cytokine.
Otkjaer
Kristian
K
Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark.
Holtmann
Helmut
H
Kragstrup
Tue Wenzel
TW
Paludan
Søren Riis
SR
Johansen
Claus
C
Gaestel
Matthias
M
Kragballe
Knud
K
Iversen
Lars
L
D020413:3' Untranslated Regions; D000841:Anisomycin / Q000494:pharmacology; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099180:Interleukin-24
D020413:3' Untranslated Regions; D000841:Anisomycin; D007093:Imidazoles; D053583:Interleukin-1beta; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D048051:p38 Mitogen-Activated Protein Kinases; D000099180:Interleukin-24; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole