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

Kate L Jeffrey, Tilman Brummer, Michael S Rolph, Sue M Liu, Nuria A Callejas, Raelene J Grumont, Corine Gillieron, Fabienne Mackay-Fisson, Shane Grey, Montserrat Camps, Christian Rommel, Steve D Gerondakis, Charles Reay Mackay

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172 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)274 - 283
Number of pages10
JournalNature Immunology
Volume7
Issue number3
DOIs
Publication statusPublished - 2006
Externally publishedYes

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