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Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1.

Mitogen-activated protein kinases facilitate many cellular processes and are essential for immune cell function. Their activity is controlled by kinases and dual-specificity phosphatases. A comprehensive microarray analysis of human leukocytes identified DUSP2 (encoding the phosphatase PAC-1) as one of the most highly induced transcripts in activated immune cells. We generated Dusp2(-/-) mice and found considerably reduced inflammatory responses in the 'K/BxN' model of rheumatoid arthritis. PAC-1 deficiency led to increased activity of Jun kinase (Jnk) but unexpected impairment of the activity of extracellular signal-regulated kinase (Erk) and the kinase p38, reduced activity of the transcription factor Elk1 and a complex of mobilized transcription factor NFAT and the AP-1 transcription factor and decreased effector immune cell function. Thus, PAC-1 is a key positive regulator of inflammatory cell signaling and effector functions, mediated through Jnk and Erk mitogen-activated protein kinase crosstalk.

Pubmed ID: 16474395

Authors

  • Jeffrey KL
  • Brummer T
  • Rolph MS
  • Liu SM
  • Callejas NA
  • Grumont RJ
  • Gillieron C
  • Mackay F
  • Grey S
  • Camps M
  • Rommel C
  • Gerondakis SD
  • Mackay CR

Journal

Nature immunology

Publication Data

March 16, 2006

Associated Grants

None

Mesh Terms

  • Animals
  • Arthritis, Experimental
  • Dual Specificity Phosphatase 2
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Inflammation
  • Leukocytes
  • MAP Kinase Kinase 4
  • Mice
  • Mitogen-Activated Protein Kinases
  • Polymerase Chain Reaction
  • Protein Phosphatase 2
  • Protein Tyrosine Phosphatases
  • Receptor Cross-Talk