Synergistic inhibitory activities of interleukin-10 and dexamethasone on human CD4+ T cells.
BACKGROUND
We have previously demonstrated that interleukin (IL)-10 synergizes with dexamethasone (Dex) in inhibiting proliferation of human T cells, stimulated in an antigen-presenting cell (APC)-dependent manner. Because IL-10 effectively inhibits APC accessory functions, the synergism could have been a result of its effect on APC. We then investigated the effects of Dex and IL-10 on T-cell subpopulations, stimulated in an APC-independent manner.


METHODS
CD4 and CD8 T cells were stimulated with anti-CD3, with or without Dex and IL-10, alone or in combination. Proliferation, glucocorticoid (GC) receptor binding, anti-CD3-induced tyrosine phosphorylation, IL-2 production, and expression of IL-2 receptor alpha, beta, and gamma chains were evaluated. The pharmacologic interactions were analyzed using the isobole method.


RESULTS
IL-10 synergized with Dex in inhibiting CD4 but not CD8 T-cell proliferation. The synergism was not associated with modifications of GC receptor number or affinity, nor with modifications of anti-CD3-induced tyrosine phosphorylation. IL-10 synergized with Dex in inhibiting IL-2 production and increased Dex inhibitory effect on the expression of the IL-2 receptor alpha chain, which is up-regulated by CD3 stimulation and IL-2. Only Dex inhibited the beta and gamma chain expression, which, interestingly, is not up-regulated by IL-2. IL-2, as well as IL-7 and IL-15, reversed the effects of IL-10 but not those of Dex.


CONCLUSIONS
IL-10 synergizes with Dex in inhibiting CD4 T-cell proliferation. Its synergizing effect is mediated by the inhibition of IL-2 production. Dex exerts additional activities, such as the inhibition of beta and gamma chain expression. Therefore, IL-10 could be useful for the enhancement of GC-based immunosuppressive therapies.
Brunetti
Mauro
M
Department of Oncology and Neuroscience, G. D'Annunzio University, Anatomia Patologica, Ospedale SS. Annunziata, Chieti, Italy. brunetti@negrisud.it
Mascetra
Nicola
N
Martelli
Nicola
N
Ranelletti
Franco O
FO
Musiani
Piero
P
Aiello
Francesca B
FB
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004357:Drug Synergism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D010766:Phosphorylation; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D005938:Glucocorticoids; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D011965:Receptors, Glucocorticoid; D015375:Receptors, Interleukin-2; D016753:Interleukin-10; D014443:Tyrosine; D003907:Dexamethasone