PKCtheta and PKA are antagonistic partners in the NF-AT transactivation pathway of primary mouse CD3+ T lymphocytes

Blood
Natascha Hermann-KleiterGottfried Baier

Abstract

We here investigate the crosstalk of PKC and PKA signaling during primary CD3(+) T-lymphocyte activation using pharmacologic inhibitors and activators in combination with our established panel of PKC isotype-deficient mouse T cells in vitro. PKCtheta and PKA inversely affect the CD3/CD28-induced IL-2 expression, whereas other PKC isotypes are dispensable in this signaling pathway. Gene ablation of PKCtheta selectively results in a profound reduction of IL-2 production; however, complete abrogation of IL-2 production in these PKCtheta(-/-) T cells was achieved only by simultaneous coactivation of the cAMP/PKA pathway in CD3(+) T cells. Conversely, the reduced IL-2 production in PKC inhibitor-treated T cells can be rescued by inhibition of the cAMP/PKA pathway in wild-type but not in PKCtheta(-/-) T cells. Mechanistically, the cAMP/PKA and PKCtheta pathways converge at the level of NF-AT, as shown by DNA binding analysis. The combined increase in PKA and decrease in PKCtheta activity leads to an enhanced inhibition of nuclear NF-AT translocation. This PKCtheta/PKA crosstalk significantly affects neither the NF-kappaB, the AP-1, nor the CREB pathways. Taken together, this opposite effect between the positive PKCtheta and the negat...Continue Reading

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Citations

May 16, 2007·The Journal of Experimental Medicine·Tobias BoppEdgar Schmitt
Mar 17, 2010·Molecular and Cellular Biology·Per Anderson, Elena Gonzalez-Rey
Sep 18, 2008·Blood·Thomas LetschkaGottfried Baier
Dec 7, 2010·Cellular Signalling·Randi Mosenden, Kjetil Taskén
Aug 18, 2009·Immunology Letters·Nikolaus ThuilleGottfried Baier
Feb 7, 2009·Current Opinion in Cell Biology·Gottfried Baier, Jürgen Wagner
Oct 20, 2015·Pathologie-biologie·Y ZaidK Kojok
Aug 5, 2010·European Journal of Immunology·Philipp A LangKarl S Lang
Dec 17, 2009·Transplant International : Official Journal of the European Society for Organ Transplantation·Gisbert WeckbeckerChristian Bruns
Oct 14, 2014·European Journal of Immunology·Patrick MöhnleSimone Kreth
Aug 19, 2015·Frontiers in Immunology·Chansavath Phetsouphanh, Anthony D Kelleher
Jul 10, 2012·Arteriosclerosis, Thrombosis, and Vascular Biology·Joel Linden, Caglar Cekic
Jun 6, 2009·The Journal of Pharmacology and Experimental Therapeutics·Jean-Pierre EvenouGottfried Baier
Dec 22, 2020·Clinical Science·Alessandra MurabitoAlessandra Ghigo
Jun 8, 2021·Frontiers in Cell and Developmental Biology·Morgane SimaoClotilde Randriamampita

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