Odd Couple: The Unexpected Partnership of Glucocorticoid Hormones and Cysteinyl-leukotrienes in the Extrinsic Regulation of Murine Bone-marrow Eosinopoiesis

Granulopoiesis in murine bone-marrow is regulated by both intrinsic and extrinsic factors (including hormones, drugs, inflammatory mediators and cytokines). Eosinophils, a minor subpopulation of circulating leukocytes, which remains better understood in its contributions to tissue injury in allergic disease than in its presumably beneficial actions in host defense, provide a striking example of joint regulation of granulopoiesis within murine bone-marrow by all of these classes of extrinsic factors. We first described the upregulation of eosinopoiesis in bone-marrow of allergen-sensitized mice following airway allergen challenge. Over the last decade, we were able to show a critical role for endogenous glucocorticoid hormones and cytokines in mediating this phenomenon through modification of cytokine effects, thereby supporting a positive association between stress hormones and allergic reactions. We have further shown that cysteinyl-leukotrienes (CysLT), a major proinflammatory class of lipid mediators, generated through the 5-lipoxygenase pathway, upregulate bone-marrow eosinopoiesis and . CysLT mediate the positive effects of drugs (indomethacin and aspirin) and of proallergic cytokines (eotaxin/CCL11 and interleukin-13) on eosinopoiesis. While these actions of endogenous GC and CysLT might seem unrelated and even antagonistic, we demonstrated a critical partnership of these mediators , shedding light on mechanisms linking stress to allergy: GC are required for CysLT-mediated upregulation of bone-marrow eosinopoiesis , but also attenuate subsequent responses to CysLT. GC and CysLT therefore work together to induce eosinophilia, but through subtle regulatory mechanisms also limit the magnitude of subsequent bone-marrow responses to allergen.