Interleukin-12 inhibits eosinophil differentiation from bone marrow stem cells in an interferon-gamma-dependent manner in a mouse model of asthma.
BACKGROUND
Intrapulmonary administration of IL-12 has been shown to inhibit the number of eosinophils in lung murine models of asthma, but the precise mechanism of this inhibition has not been reported. The purpose of this study was to examine whether IL-12 treatment inhibits bone marrow eosinophilopoiesis, and to elucidate the role of IFN-gamma in this process.


OBJECTIVE
To elucidate the in vivo and in vitro effects of IL-12 on eosinophil differentiation from murine bone marrow (BM) stem cells, and to examine the mechanistic role of IFN-gamma in this process.


METHODS
Allergen-sensitized BALB/c mice were administered low doses of intranasal IL-12 at the time of allergen challenge, and the number of eosinophils in BM was determined 3 days later. The direct actions of IL-12 on eosinophil differentiation from BM cells were determined in vitro. The mechanistic role of IFN-gamma was assessed by measuring IFN-gamma induction by IL-12 in BM cell cultures, and through the use of IFN-gamma KO mice.


RESULTS
Treatment of allergic mice with intrapulmonary IL-12 (1 ng or 10 ng) reduced eosinophils in BM by 43%. Culture of BM cells from allergen-sensitized mice with IL-3 + IL-5 induced eosinophil differentiation in vitro. Addition of IL-12 to these cultures inhibited eosinophil differentiation, with maximal inhibition (45%) occurring at 10 ng/mL IL-12 concentration. IL-12 induced IFN-gamma production from BM cultures, and failed to inhibit eosinophil differentiation in IFN-gamma-knockout mice, indicating a critical mechanistic role for IFN-gamma.


CONCLUSIONS
This study demonstrates that IL-12 selectively inhibits BM eosinophilopoiesis, and that this effect is mediated by IFN-gamma. Intrapulmonary IL-12 has suppressive effects on BM eosinophilopoiesis that may represent a novel mechanism contributing to the anti-eosinophilic effects of IL-12 in allergic airway disease.
Rais
M
M
Department of Internal Medicine, Division of Allergy and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Wild
J S
JS
Choudhury
B K
BK
Alam
R
R
Stafford
S
S
Dharajiya
N
N
Sur
S
S
D000818:Animals; D001249:Asthma / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000494:pharmacology*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018448:Models, Immunological
D015848:Interleukin-5; D018664:Interleukin-12; D007371:Interferon-gamma