TY  - JOUR
AU  - Wabnitz, Guido H
AU  - Kirchgessner, Henning
AU  - Jahraus, Beate
AU  - Umansky, Ludmila
AU  - Shenolikar, Shirish
AU  - Samstag, Yvonne
TI  - PP1α and Cofilin regulate nuclear translocation of NFkB and promote expression of the anti-inflammatory cytokine IL-10 by T-cells.
JO  - Molecular and cellular biology
VL  - 38
IS  - 22
SN  - 1098-5549
CY  - Washington, DC
PB  - Soc.
M1  - DKFZ-2018-01464
SP  - e00041-18
PY  - 2018
AB  - While several protein serine-threonine kinases control cytokine production by T-cells, the roles of serine-threonine phosphatases are largely unexplored. Here, we analysed the involvement of protein phosphatase-1α (PP1α) in cytokine synthesis following costimulation of primary human T-cells. SiRNA-mediated knock-down of PP1α (PP1KD) or expression of a dominant-negative PP1α (D95N-PP1) drastically diminished IL-10 production. Focusing on a key transcriptional activator of human IL-10, we demonstrate that nuclear translocation of NF-kB was significantly inhibited in PP1KD or D95N-PP1 cells. Interestingly, knockdown of cofilin, a known substrate of PP1 containing a nuclear localization signal, also prevented nuclear accumulation of NF-kB. Expression of a constitutively active non-phosphorylatable S3A-cofilin in D95N-PP1 cells restored nuclear translocation of NF-kB and IL-10 expression. Sub-population analysis revealed that defective nuclear translocation of NF-kB was most prominent in CD4+CD45RA-CXCR3- T-cells that included IL-10-producing TH2 cells. Together these findings reveal novel functions for PP1α and its substrate cofilin in T-cells namely the regulation of the nuclear translocation of NF-kB and promotion of IL-10 production. These data suggest that stimulation of PP1α could limit the overwhelming immune responses seen in chronic inflammatory diseases.
LB  - PUB:(DE-HGF)16
C6  - pmid:30181394
DO  - DOI:10.1128/MCB.00041-18
UR  - https://inrepo02.dkfz.de/record/137584
ER  -