Open AccessCa 2+ ‐induced p38/SAPK signalling inhibited by the immunosuppressant cyclosporin A in human peripheral blood mononuclear cells
Author(s) -
Kreideweiß Stefan,
Ahlers Christoph,
Nordheim Alfred,
Rühlmann Andreas
Publication year - 1999
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1046/j.1432-1327.1999.00830.x
Subject(s) - ionomycin , creb , p38 mitogen activated protein kinases , kinase , mapk/erk pathway , peripheral blood mononuclear cell , phosphorylation , microbiology and biotechnology , intracellular , transcription factor , protein kinase a , protein kinase c , chemistry , biology , biochemistry , in vitro , gene
To understand the effects of the immunosuppressant cyclosporin A (CsA) on Ca 2+ ‐mediated intracellular signalling pathways in human peripheral blood mononuclear cells (PBMCs), we investigated its effects on the activity profiles of mitogen‐activated protein kinase (MAPK) cascades. PBMCs, or subpopulations thereof, were simultaneously stimulated with a phorbol ester and the calcium ionophore ionomycin, in the presence or absence of therapeutic concentrations of CsA. In these primary human cells, CsA significantly inhibited PMA/ionomycin‐mediated and ionomycin‐mediated activation of the MAPK kinase MKK6, as well as its downstream kinases SAPK2a (p38α) and MAPKAP‐K2. PMA/ionomycin treatment also mediated activation of SAPK1 (JNKs) which was inhibited by CsA. Treatment with ionomycin alone also resulted in CsA‐sensitive activation of SAPK1. With regard to transcription factors targeted by the Ca 2+ ‐induced MAPK signalling network, we found CsA to inhibit the ionomycin‐mediated phosphorylation of ATF2 at Thr71. We identified the heterodimeric transcription factor ATF2/CREB as constitutively binding to the essential cAMP response element (CRE) site within the Ca 2+ ‐regulated DNA polymerase β promoter and contributing to the activation of this promoter. Our data implicate ATF2 phosphorylation status as a nuclear sensor within PBMCs that monitors converging intracellular Ca 2+ ‐signalling pathways.