Adalimumab therapy rapidly inhibits p38 mitogen-activated protein kinase activity in lesional psoriatic skin preceding clinical improvement

作者：Soegaard Madsen L; Johansen C; Iversen L; Kragballe K^*

来源：British Journal of Dermatology, 2010, 162(6): 1216-1223.

DOI：10.1111/j.1365-2133.2010.09706.x

• adalimumab
• p38 mitogen-activated protein kinase
• psoriasis

Background The pathogenesis of psoriasis and the mechanisms of action of antitumour necrosis factor (TNF)-alpha therapies are incompletely understood. Objectives To investigate the early molecular effects of adalimumab in psoriatic skin.
Methods Biopsies taken from patients with psoriasis were examined before and after the onset of adalimumab therapy. TNF-alpha protein level and mRNA expression were measured by enzyme-linked immunosorbent assay and quantitative reverse transcription-polymerase chain reaction, respectively. The activities of p38 mitogen-activated protein kinase (MAPK) and extracellular regulated kinase 1 and 2 (ERK1/2) as well as the downstream kinases MAPK-activated protein kinase 2 (MK2) and mitogen-and stress-activated protein kinase 1 and 2 (MSK1/2) were measured by Western blot analyses.
Results We demonstrated that clinical and histological improvements were detected from day 14. The increased activity of p38 MAPK in lesional psoriatic skin was significantly inhibited by adalimumab already at day 4. The activities of ERK1/ 2, MSK1/2 and MK2 were reduced at the end of study (day 84) when the level of TNF-alpha in lesional psoriatic skin reached the nonlesional level, and the Psoriasis Area and Severity Index score was reduced.
Conclusions The rapid inhibition of p38 MAPK by adalimumab in lesional psoriatic skin preceded clinical and histological improvements, demonstrating an association between TNF-alpha neutralization and p38 MAPK inhibition. Thus, inhibition of p38 MAPK may be a novel mechanism by which adalimumab mediates its antipsoriatic effect.

• 出版日期2010-6