Activation of cGMP-dependent protein kinase I beta inhibits interleukin 2 release and proliferation of T cell receptor-stimulated human peripheral T cells

Several major functions of type I cGMP-dependent protein kinase (cGK I) hav e been established in smooth muscle cells, platelets, endothelial cells, an d cardiac myocytes, Here we demonstrate that cGK I beta is endogenously exp ressed in freshly purified human peripheral blood T lymphocytes and inhibit s their proliferation and interleukin 2 release. Incubation of human T cell s with the NO donor, sodium nitroprusside, or the mem brane-permeant cGMP a nalogs PET-cGMP and 8-pCPT-cGMP, activated cGK I and produced (i) a distinc t pattern of phosphorylation of vasodilator-stimulated phosphoprotein, (ii) stimulation of the mitogen-activated protein kinases ERK1/2 and p38 kinase , and, upon anti-CD3 stimulation, (iii) inhibition of interleukin 2 release and (iv) inhibition of cell proliferation. cGK I was lost during in vitro culturing of primary T cells and was not detectable in transformed T cell l ines. The proliferation of these cGK I-deficient cells was not inhibited by even high cGMP concentrations indicating that cGK I, but not cGMP-regulate d phosphodiesterases or channels, cAMP-dependent protein kinase, or other p otential cGMP mediators, was responsible for inhibition of T cell prolifera tion, Consistent with this, overexpression of cGK I beta, but not an inacti ve cGK I beta mutant, restored cGMP-dependent inhibition of cell proliferat ion of Jurkat cells, Thus, the NO/cGMP/cGK signaling system is a negative r egulator of T cell activation and proliferation and of potential significan ce for counteracting inflammatory or lymphoproliferative processes.