Activation of cGMP-dependent protein kinase Ibeta 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) have been established in smooth muscle cells, platelets, endothelial cells, and cardiac myocytes. Here we demonstrate that cGK Ibeta is endogenously expressed in freshly purified human peripheral blood T lymphocytes and inhibits their proliferation and interleukin 2 release. Incubation of human T cells with the NO donor, sodium nitroprusside, or the membrane-permeant cGMP analogs PET-cGMP and 8-pCPT-cGMP, activated cGK I and produced (i) a distinct 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 lines. The proliferation of these cGK I-deficient cells was not inhibited by even high cGMP concentrations indicating that cGK I, but not cGMP-regulated phosphodiesterases or channels, cAMP-dependent protein kinase, or other potential cGMP mediators, was responsible for inhibition of T cell proliferation. Consistent with this, overexpression of cGK Ibeta, but not an inactive cGK Ibeta mutant, restored cGMP-dependent inhibition of cell proliferation of Jurkat cells. Thus, the NO/cGMP/cGK signaling system is a negative regulator of T cell activation and proliferation and of potential significance for counteracting inflammatory or lymphoproliferative processes.
Fischer
T A
TA
Department of Medicine II, University of Mainz, D-55101 Mainz, Germany.
Palmetshofer
A
A
Gambaryan
S
S
Butt
E
E
Jassoy
C
C
Walter
U
U
Sopper
S
S
Lohmann
S M
SM
D017398:Alternative Splicing; D001792:Blood Platelets / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002463:Cell Membrane Permeability; D002469:Cell Separation; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008840:Microfilament Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D000098662:Vasodilator-Stimulated Phosphoprotein
D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D007376:Interleukin-2; D008840:Microfilament Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D000098662:Vasodilator-Stimulated Phosphoprotein; D009599:Nitroprusside; D000242:Cyclic AMP; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; C569718:PRKG1 protein, human; D020928:Mitogen-Activated Protein Kinases; D006152:Cyclic GMP