IL-12 p40 messenger RNA expression in target organs during acute graft-versus-host disease. Possible involvement of IFN-gamma.
The onset of acute graft-vs-host disease (aGVHD) is accompanied by macrophage (M phi) priming and the presence of bacteria-derived LPS in the sera of transplanted animals. Priming of M phi occurs during aGVHD despite the suppression of T cell function. We have investigated whether IL-12 mediates the continued production of IFN-gamma during the state of T cell immunosuppression that accompanies aGVHD. Acute GVHD was induced in nonirradiated AxC57BL/6F1 mice by the injection of C57BL/6 lymphoid cells. Despite T cell immunosuppression, M phi became primed, as shown by their expression of inducible nitric oxide synthase mRNA and their production of nitric oxide in response to LPS. Continual exposure to IFN-gamma was required to maintain a primed state in M phi during aGVHD. IL-12 p40 peptide mRNA was increased in M phi purified from animals undergoing aGVHD 14 days after transplantation. Target organs of aGVHD, including thymus, salivary gland, and lung, showed increased IFN-gamma mRNA between days 7 and 14 after transplantation. The increase was accompanied by an induction of mRNA for the p40 peptide of IL-12 and inducible nitric oxide synthase within the target organs. These results provide evidence for localized production of IFN-gamma within aGVHD target organs and suggest that it is mediated by LPS-induced production of IL-12 by M phi. Our data elucidate the mechanism of activation of M phi during aGVHD that results in TNF-alpha and nitric oxide production and delineates the effector role of M phi in the pathology of aGVHD.
Kichian
K
K
Department of Physiology, McGill University, Montreal, Quebec, Canada.
Nestel
F P
FP
Kim
D
D
Ponka
P
P
Lapp
W S
WS
D000208:Acute Disease; D000818:Animals; D001483:Base Sequence; D003433:Crosses, Genetic; D004790:Enzyme Induction; D006086:Graft vs Host Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008221:Lymphoid Tissue / Q000637:transplantation*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D009928:Organ Specificity; D012333:RNA, Messenger / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018664:Interleukin-12; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase