Essential roles of endogenous glucocorticoids and TNF/TNFR1 in promoting bone-marrow eosinopoiesis in ovalbumin-sensitized, airway-challenged mice.
OBJECTIVE
Stress mechanisms paradoxically contribute to allergic episodes in humans and mice. Glucocorticoids (GC) and interleukin (IL)-5 synergically upregulate murine bone-marrow eosinophil production. Here we explored the role of endogenous GC in allergen-stimulated bone-marrow eosinophil production in ovalbumin-sensitized/challenged mice.


METHODS
In BALB/c or C57BL/6 mice, sensitized and intranasally challenged with ovalbumin, we monitored eosinophil numbers in freshly harvested or cultured bone-marrow, and plasma corticosterone levels. Metyrapone (MET) was used to inhibit GC synthesis, and RU486 to block GC actions. In sensitized mice challenged intraperitoneally, we examined the relationship between eosinophilia of bone-marrow and peritoneal cavity, in the absence or presence of RU486. In experiments involving in vivo neutralization of tumor necrosis factor-α (TNF) by specific antibodies, or using mice which lack functional type I TNF receptors (TNFRI), we evaluated the relationship between TNF blockade, corticosterone levels, RU486 or MET treatment and challenge-induced bone-marrow eosinophilia.


RESULTS
RU486 or MET pretreatments abolished challenge-induced increases in eosinophil numbers in bone-marrow (in vivo and ex vivo), and in the peritoneal cavity. MET, but not RU486, prevented the challenge-induced increase in corticosterone levels. Challenge-induced bone-marrow eosinophilia and corticosterone surge were abolished in TNFRI-deficient mice. Anti-TNF-treatment very effectively prevented challenge-induced bone-marrow eosinophilia, in the absence of RU486 or MET, but had no independent effect in the presence of either drug.


CONCLUSIONS
Endogenous GC was essential for allergen challenge-induced increases in eosinophil numbers inside bone-marrow. This effect required TNF and TNFRI, which suggests an immunoendocrine mechanism.
Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil.
Daniela
D
Masid-de-Brito
Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil. Electronic address: pxelsas@micro.ufrj.br.
Pedro
P
Xavier-Elsas
Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil; Depto Pediatria, Instituto Fernandes Figueira, FIOCRUZ, Rio de Janeiro, Brazil.
Ricardo Alves
RA
Luz
Depto Pediatria, Instituto Fernandes Figueira, FIOCRUZ, Rio de Janeiro, Brazil.
Túlio
T
Queto
Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil.
Cássio Luiz Coutinho
CL
Almeida da Silva
Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Brazil.
Rodrigo Soares
RS
Lopes
Depto Pediatria, Instituto Fernandes Figueira, FIOCRUZ, Rio de Janeiro, Brazil.
Bruno Marques
BM
Vieira
Depto Pediatria, Instituto Fernandes Figueira, FIOCRUZ, Rio de Janeiro, Brazil.
Maria Ignez Capella
MI
Gaspar-Elsas
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D004802:Eosinophilia / Q000378:metabolism*; D004804:Eosinophils / Q000378:metabolism*; D005260:Female; D005938:Glucocorticoids / Q000096:biosynthesis / Q000378:metabolism*; D007249:Inflammation / Q000503:physiopathology; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D010529:Peritoneal Cavity; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D005938:Glucocorticoids; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone; D010047:Ovalbumin; D003345:Corticosterone; D008797:Metyrapone
Allergic inflammation; Bone-marrow; Eosinophils; Glucocorticoids; TNF-α