Cytokinins are
plant hormones that play an integral role in multiple aspects of plant growth and development. The
biological functions of
cytokinins in mammalian systems are, however, largely uncharacterized. The naturally occurring
cytokinin zeatin riboside has recently been demonstrated to activate the mammalian
adenosine A(2A) receptor, which is broadly expressed by various cell types including immune system cells, with the activation of the A(2A)R playing a role in the regulation of cells involved in both innate and adaptive immunity. We show for the first time that
zeatin riboside modulates mammalian immune system activity via an A(2A)R-dependent mechanism. Specifically,
zeatin riboside treatment induces the production of cyclic
adenosine monophosphate (cAMP) by T lymphocytes and inhibits the production by CD3(+)CD4(+) T cells of
interferon (IFN)-γ,
IL-2,
tumor-necrosis factor (TNF)-α,
IL-4 and
IL-13, and the production by CD3(+)CD8(+) T cells of IFN-γ,
IL-2 and TNF-α. Additionally, the upregulation of CD25, CD69 and
CD40L by activated T lymphocytes is modulated by
zeatin riboside.
Zeatin riboside treatment also potently inhibits thioglycollate-induced peritoneal
leukocytosis. The immunomodulatory activities of
zeatin riboside are blocked by co-treatment with the selective A(2A)R antagonist
ZM241385. These data suggest that
zeatin riboside possesses therapeutic potential as a mammalian immunomodulatory agent.