Suppression of B-cell proliferation to lipopolysaccharide is mediated through induction of the nitric oxide pathway by tumor necrosis factor-alpha in mice with acute graft-versus-host disease.
Graft-versus-host disease (GVHD) is associated with impaired B-cell responses. We investigated the mechanism of impaired proliferation of B cells in response to the mitogen lipopolysaccharide (LPS) by analyzing the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), both of which have independently been described as important effector mechanisms in the pathogenesis of acute GVHD. A threefold decrease of mature surface Ig-positive (slg+) B cells was observed in GVHD spleens isolated 2 weeks after transplant. However, proliferation of these cells in response to LPS was suppressed by more than 35-fold. Activated GVHD splenocytes secreted large amounts of TNF-alpha and NO in culture. Neutralization of TNF-alpha with anti-TNF-alpha antibody (Ab) both abrogated NO production and restored LPS-induced proliferation of B cells to levels found in non-GVHD control mice. The specific inhibition of NO synthesis with LG-monomethyl-arginine (NMMA) restored splenocyte responses but did not significantly reduce TNF-alpha levels, showing that TNF-alpha per se did not cause immunosuppression. These data show that, during GVHD, induction of the NO pathway is an important mechanism that mediates B-cell hyporesponsiveness to LPS and that this pathway is induced by TNF-alpha.
Falzarano
G
G
Division of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, MA, USA.
Krenger
W
W
Snyder
K M
KM
Delmonte
J
J
Karandikar
M
M
Ferrara
J L
JL
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide