Preferential inhibition of the mRNA expression of p38 mitogen-activated protein kinase regulated cytokines in psoriatic skin by anti-TNFα therapy.
BACKGROUND
Anti-TNFα therapies are well established for severe psoriasis; however, their mechanism of action in disease resolution is not fully understood. p38 mitogen-activated protein kinase (MAPK) is a kinase known to play a key role in the pathogenesis of psoriasis.


OBJECTIVE
To elucidate the early effects of adalimumab, a human monoclonal anti-TNFα antibody, on the expression of interleukins in psoriatic skin.


METHODS
Biopsies from patients with psoriasis were examined before and after the start of adalimumab therapy. mRNA expression of cytokines were measured with quantitative polymerase chain reaction. p38 MAPK and signal transducer and activator of transcription 3 (STAT3) were analysed by Western blotting and immunofluorescence analyses, and IL-17A and IL-17C were examined with immunohistochemistry.


RESULTS
The increased mRNA level of IL-1β, IL-8, IL-17C and IL-20 in lesional psoriatic skin was already significantly reduced 4 days after the start of adalimumab treatment, i.e. before clinical and histological improvement was detectable. The mRNA expression of the Th17-derived cytokines IL-17A, IL-17F and IL-22 as well as the dendritic cell product IL-23/IL-12 (p40) were not significantly reduced until 2 weeks after the start of treatment, whereas the mRNA expression of IL-23 (p19) and the Th1 cytokines IFN-γ and IL-2 were reduced late in disease resolution. IL-1β, IL-8 and IL-20 are all known to be regulated by p38 MAPK. IL-17C was produced by cultured human keratinocytes and this production was also mediated by a p38 MAPK dependent mechanism. Moreover, the early effects of adalimumab included the phosphorylation of p38 MAPK, but not STAT3 phosphorylation.


CONCLUSIONS
This study indicates that an important mechanism of action of anti-TNFα therapy in psoriasis is a reduction in p38 MAPK phosphorylation and a subsequent decrease in the expression of p38 MAPK regulated genes.
Johansen
C
C
Department of Dermatology, Aarhus University Hospital, P P Orumsgade 11, DK-8000 Aarhus C, Denmark. claus.johansen@ki.au.dk
Vinter
H
H
Soegaard-Madsen
L
L
Olsen
L R
LR
Steiniche
T
T
Iversen
L
L
Kragballe
K
K
D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015153:Blotting, Western; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D007378:Interleukins / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000068879:Adalimumab