ABSTRACT
We describe the potent effect of myriadenolide (Myr), a naturally occurring labdane diterpene, in promoting the production of eosinophils in cultured bone-marrow from several inbred mouse strains. This enhancing effect is lineage-selective and requires the eosinophil growth factors, Interleukin(IL)-5 or GM-CSF. Myr acts over a very low concentration range (10-10-10-14â¯M), if added at the beginning of the cell cultivation. Its enhancing effect increases between 24â¯h and 10â¯days of culture. We used both pharmacological and genetical tools to analyze its mechanism of action. Several lines of evidence show that the enhancing effect of Myr requires functional integrity of the 5-lipoxygenase (5-LO) pathway, and of CysLT1 receptors, which transduce the effects of cysteinyl-leukotrienes generated through this pathway. Myr also protects developing eosinophils from apoptosis induced by exogenous prostaglandin E2 (PGE2), but not by NO, indicating that it acts upstream of NO in the PGE2-initiated proapoptotic pathway which requires iNOS and CD95. Exposure to NO concentrations insufficient to induce apoptosis abolished the ability of eosinophils to respond to Myr, suggesting the involvement of a NO-sensitive cellular target. Myr has potential as a chemically defined research tool, which can be used to generate large numbers of eosinophils, thereby overcoming current limitations in the biochemical and molecular biological study of murine eosinophils, which has so far depended on complex, labor-intensive and long-term culture protocols for in vitro expansion. SUMMARY: Potent enhancing effects of Myr on eosinophil production in bone marrow stimulated by GM-CSF and IL-5 are mediated by the 5-LO pathway.
Subject(s)
Cysteine/metabolism , Diterpenes/pharmacology , Eosinophils/drug effects , Leukotrienes/metabolism , Animals , Arachidonate 5-Lipoxygenase/metabolism , Bone Marrow/drug effects , Cells, Cultured , Dinoprostone/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Interleukin-5/pharmacology , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred CBA , Nitric Oxide Donors/pharmacology , Receptors, Leukotriene/metabolism , Signal Transduction/drug effectsABSTRACT
Flavonoids are polyphenolic compounds of natural occurrence produced by plants that are largely consumed both for therapeutic purposes and as food. Experimental data have shown that many flavonoids could inhibit thyroperoxidase activity, decreasing thyroid hormones levels thus increasing TSH and causing goiter. In humans, infants fed with soy formula have been shown to develop goiter. However, in post-menopausal women soy intake did not affect thyroid function. In thyroid tumor cell line, flavonoids were shown to inhibit cell growth, but they can also decrease radioiodine uptake, that could reduce the efficacy of radioiodine therapy. Flavonoids could also affect the availability of thyroid hormones to target tissues, by inhibiting deiodinase activity or displacing T4 from transthyretin. Thus, flavonoids have been shown to interfere with many aspects of the thyroid hormones synthesis and availability in in vivo and in vitro models. In the present article, we review and synthesize the literature on the effects of flavonoids on thyroid and discuss the possible relevance of these effects for humans.