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

Br J Dermatol. 2010 Jun;162(6):1216-23. doi: 10.1111/j.1365-2133.2010.09706.x. Epub 2010 Mar 25.

Abstract

Background: The pathogenesis of psoriasis and the mechanisms of action of antitumour necrosis factor (TNF)-α 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-α 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-α 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-α neutralization and p38 MAPK inhibition. Thus, inhibition of p38 MAPK may be a novel mechanism by which adalimumab mediates its antipsoriatic effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adalimumab
  • Anti-Inflammatory Agents / therapeutic use*
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Biopsy
  • Blotting, Western
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Psoriasis / drug therapy*
  • Psoriasis / enzymology
  • RNA, Messenger / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Inflammatory Agents
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Intracellular Signaling Peptides and Proteins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases
  • RPS6KA4 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • Adalimumab