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.
|Authors||Jeffrey, K. L.; Brummer, T.; Rolph, M. S.; Liu, S. M.; Callejas, N. A.; Grumont, R. J.; Gillieron, C.; Mackay, F.; Grey, S.; Camps, M.; Rommel, C.; Gerondakis, S. D.; Mackay, C. R.|
|Publisher Name||NATURE IMMUNOLOGY|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16474395|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/2068|