title: p38 inhibition and not MK2 inhibition enhances the secretion of chemokines from TNF-α activated rheumatoid arthritis fibroblast-like synoviocytes.
abstract: OBJECTIVE
  For many years the p38 MAP kinase (MAPK) has been a major anti-inflammatory target for the development of an oral therapy for rheumatoid arthritis (RA). However, disappointing results from Phase II clinical studies suggest that adaptations may occur, which allow escape from blockade of the p38 pathway. In this study we investigated whether p38 inhibition mediated JNK activation represents such an escape mechanism.
  
  
  METHODS
  Interaction between the JNK and p38 pathways was studied in TNF-α stimulated THP-1 monocytes, primary macrophages and fibroblast-like synoviocytes from OA and RA patients using pharmacological inhibitors and siRNAs.
  
  
  RESULTS
  TNF-α induced phosphorylation of JNK and c-Jun was sustained by p38 inhibitors in monocytes, primary macrophages and FLS. Upregulation of Mip1α, Mip1β and IL-8 mRNAs and protein were observed upon p38 inhibition. More importantly, inhibition of MK2, the substrate of p38 did not sustain JNK activation upon TNF-α activation and did not elevate Mip1α, Mip1β and IL-8 chemokines as compared to TNF-α alone. In this study, TNF-α or IL-1β induced JNK activation is sustained by p38 inhibition, resulting in enhanced chemokine secretion.
  
  
  CONCLUSIONS
  Based on the suggested role of these chemokines in RA pathogenesis, the upregulation of these chemokines may provide an explanation for the lack of efficacy of p38 inhibitors in Phase II. The absence of any effect of MK2 inhibition in our models on this mechanism, while coming with similar efficacy on blocking p38, provides support for further investigations to reveal the potential of MK2 inhibition as a novel treatment of RA.
authors.affiliation: Immune Therapeutics, Merck Research Laboratories, the Netherlands. j.dulos@live.com
authors.forename: J
authors.initials: J
authors.lastname: Dulos
authors.forename: F P G
authors.initials: FP
authors.lastname: Wijnands
authors.forename: J A J
authors.initials: JA
authors.lastname: van den Hurk-van Alebeek
authors.forename: M J H
authors.initials: MJ
authors.lastname: van Vugt
authors.forename: J A C
authors.initials: JA
authors.lastname: Rullmann
authors.forename: J-J G
authors.initials: JJ
authors.lastname: Schot
authors.forename: M W G D M
authors.initials: MW
authors.lastname: de Groot
authors.forename: J L
authors.initials: JL
authors.lastname: Wagenaars
authors.forename: R
authors.initials: R
authors.lastname: van Ravestein-van Os
authors.forename: R L
authors.initials: RL
authors.lastname: Smets
authors.forename: P M
authors.initials: PM
authors.lastname: Vink
authors.forename: C L
authors.initials: CL
authors.lastname: Hofstra
authors.forename: R L H
authors.initials: RL
authors.lastname: Nelissen
authors.forename: H
authors.initials: H
authors.lastname: van Eenennaam
mesh_terms: D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D002460:Cell Line; D018925:Chemokines / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009000:Monocytes / Q000166:cytology; D009281:Naphthalenes / Q000494:pharmacology; D061251:Primary Cell Culture; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2; D010671:Phenylurea Compounds
chemical_list: D018925:Chemokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C452139:doramapimod; D010671:Phenylurea Compounds; C093642:SB 203580