By contrast, a sustained increase in bone-marrow eosinophil production (eosinopoiesis), as well as prolonged survival in the peripheral inflammatory site, is believed to promote chronic allergic inflammation in humans and mice [8-10].
There is interest in characterizing the mechanisms that ensure the selective increases in eosinopoiesis, both inside and outside the bone-marrow, following exposure to allergen challenge in sensitized subjects.
In bone-marrow cultures stimulated by interleukin (IL)-5, the major eosinopoiesis-promoting cytokine and lineage-specific survival factor [1-3, 7, 17], exogenously added CysLT, significantly enhance eosinopoiesis [19, 20].
Even though IL-5 signals through a common [beta] chain ([beta]c), which is also used by GM-CSF and IL-3 to signal through their own receptors, IL-5, unlike the other cytokines in this group, is preferentially expressed in the eosinophil lineage and is necessary for physiological eosinopoiesis .
Eosinopoiesis in liquid culture was strictly dependent on IL-5, and culture conditions were adequate for demonstrating both enhancing and suppressive effects [9, 29, 30].
The Effectiveness of DEC in Suppressing Eosinopoiesis in Bone-Marrow of Sensitized/Challenged Mice Depends on 5LO.
iNOS-deficient bone-marrow is nevertheless susceptible to inhibition by NO, as shown by the ability of NO-releasing chemicals to suppress eosinopoiesis, indicating that NO acts downstream from PGE2.
On the other hand, PGE2-induced suppression of eosinopoiesis is effectively blocked by cysteinyl-leukotrienes (CysLT), which are important mediators of inflammation in asthmatic lungs .
We have therefore compared the effects of a widely used [beta]-adrenergic ligand (isoproterenol) and of other cAMP-inducing/mimetic agents on eosinopoiesis with those of PGE2 and addressed the roles played by adenylyl cyclase, PKA, iNOS, NO, CD95L/CD95, and terminal caspases, in the actions of these modulators and mediators.
Because it has been recently reported that preexposure for 4 days to flt3L plus SCF primes bone-marrow for increased eosinopoiesis in the presence of IL-5 , we further examined the effect of priming on the suppressive activity of both ligands, comparing cultures of primed and unprimed bone-marrow cells cultured for comparable periods (Figure 3(d)).
This is, to our knowledge, the first study to establish a sequence of events strictly required for suppression of eosinopoiesis by any soluble ligand.