Nature Immunology 7, 274 - 283 (2006)
Published online: 12 February 2006; | doi:10.1038/ni1310
Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1Kate L Jeffrey1, 2, Tilman Brummer1, Michael S Rolph1, 2, Sue M Liu1, 2, Nuria A Callejas1, Raelene J Grumont3, Corine Gillieron4, Fabienne Mackay1, Shane Grey1, Montserrat Camps4, Christian Rommel4, Steve D Gerondakis3
& Charles R Mackay1, 21
Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia. 2
Cooperative Research Centre for Asthma, Darlinghurst, Sydney, New South Wales 2010, Australia. 3
Walter and Eliza Hall Institute, Parkville, Melbourne, Victoria 3050, Australia. 4
Serono Pharmaceutical Research Institute, Serono International, Geneva 1228, Switzerland.
Correspondence should be addressed to Steve D Gerondakis gerondakis@wehi.edu.au or Charles R Mackay c.mackay@garvan.org.au 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.
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