CD28 ligation prevents bacterial toxin-induced septic shock in mice by inducing IL-10 expression.
The pathogenesis of septic shock is due mainly to bacterial toxin stimulation of the immune system, resulting in an excessive production of proinflammatory cytokines. TNF-alpha has been implicated as a major mediator in septic shock. Coinjection of D-galactosamine and LPS or staphylococcal enterotoxin B induced a rapid-onset, low-dose form of septic shock syndrome and ultimately led to death. We found that both the septic shock syndrome and death could be prevented by administration of anti-CD28 Ab. The protection induced by anti-CD28 Ab was associated with a decrease in TNF-alpha levels in the circulation. In addition, serum from anti-CD28 Ab-treated mice was capable of inhibiting the production of TNF-alpha by bone marrow-derived macrophages following treatment with LPS, indicating that anti-CD28 Ab induced production of soluble factors that subsequently inhibited the production of TNF-alpha. We confirmed that one of the factors present in serum was IL-10, because anti-CD28 Ab treatment stimulated the expression of IL-10, both in splenocytes and in T cell lines. Furthermore, injection of anti-IL-10 Abs could abolish the protective effect of anti-CD28 Ab on septic shock. Anti-IL-10 Ab could also suppress the anti-CD28 Ab-induced inhibition of TNF-alpha production, either in vivo or in vitro. Thus, we conclude that ligation of CD28 induces expression of IL-10, which in turn suppresses TNF-alpha production and prevents septic shock.
Wang
R
R
Department of Immunology, American Red Cross, Rockville, MD 20855, USA.
Fang
Q
Q
Zhang
L
L
Radvany
L
L
Sharma
A
A
Noben-Trauth
N
N
Mills
G B
GB
Shi
Y
Y
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D004768:Enterotoxins / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D012772:Shock, Septic / Q000276:immunology / Q000517:prevention & control*; D015398:Signal Transduction / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology
D000906:Antibodies; D018106:CD28 Antigens; D004768:Enterotoxins; D008070:Lipopolysaccharides; D016753:Interleukin-10; C031818:enterotoxin B, staphylococcal