The cGMP/protein kinase G pathway contributes to dihydropyridine-sensitive calcium response and cytokine production in TH2 lymphocytes.
Th2 lymphocytes differ from other CD4+ T lymphocytes not only by their effector tasks but also by their T cell receptor (TCR)-dependent signaling pathways. We previously showed that dihydropyridine receptors (DHPR) involved in TCR-induced calcium inflow were selectively expressed in Th2 cells. In this report, we studied whether cGMP-dependent protein kinase G (PKG) activation was implicated in the regulation of DHPR-dependent calcium response and cytokine production in Th2 lymphocytes. The contribution of cGMP in Th2 signaling was supported by the following results: 1) TCR activation elicited cGMP production, which triggered calcium increase responsible for nuclear factor of activated T cell translocation and Il4 gene expression; 2) guanylate cyclase activation by nitric oxide donors increased intracellular cGMP concentration and induced calcium inflow and IL-4 production; 3) reciprocally, guanylate cyclase inhibition reduced calcium response and Th2 cytokine production associated with TCR activation. In addition, DHPR blockade abolished cGMP-induced [Ca2+]i increase, indicating that TCR-induced DHP-sensitive calcium inflow is dependent on cGMP in Th2 cells. Th2 lymphocytes from PKG1-deficient mice displayed impaired calcium signaling and IL-4 production, as did wild-type Th2 cells treated with PKG inhibitors. Altogether, our data indicate that, in Th2 cells, cGMP is produced upon TCR engagement and activates PKG, which controls DHP-sensitive calcium inflow and Th2 cytokine production.
Gomes
Bruno
B
INSERM, 1U563, Centre de Physiopathologie de Toulouse Purpan, F-31024 Toulouse Cedex 3, France.
Savignac
Magali
M
Cabral
Marilena Djata
MD
Paulet
Pierre
P
Moreau
Marc
M
Leclerc
Catherine
C
Feil
Robert
R
Hofmann
Franz
F
Guéry
Jean-Charles
JC
Dietrich
Gilles
G
Pelletier
Lucette
L
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry*; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004095:Dihydropyridines / Q000737:chemistry*; D006162:Guanylate Cyclase / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D050778:NFATC Transcription Factors / Q000378:metabolism; D017942:Nitric Acid / Q000378:metabolism; D018418:Th2 Cells
D016207:Cytokines; D004095:Dihydropyridines; D050778:NFATC Transcription Factors; D015847:Interleukin-4; D017942:Nitric Acid; C038806:1,4-dihydropyridine; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D002118:Calcium