B7-H3 augments the inflammatory response and is associated with human sepsis.
B7-H3, a new member of the B7 superfamily, acts as both a T cell costimulator and coinhibitor, and thus plays a key role in the regulation of T cell-mediated immune responses. However, it is unclear whether B7-H3 is involved in the innate immune monocyte/macrophage-mediated inflammatory response. In this paper, we show that, although B7-H3 alone failed to stimulate proinflammatory cytokine release from murine macrophages, it strongly augmented both LPS- and bacterial lipoprotein-induced NF-kappaB activation and inflammatory response. This occurred in both a TLR4- and TLR2-dependent manner. Blockage of B7-H3 in vivo attenuated LPS-induced proinflammatory cytokine release and endotoxic shock-related lethality. Furthermore, we found that patients diagnosed with sepsis, in contrast to healthy individuals, exhibited significant levels of raised plasma soluble B7-H3 (sB7-H3) and that this level correlated with the clinical outcome and levels of plasma TNF-alpha and IL-6. In addition, a putative receptor for B7-H3 was detected on monocytes and peritoneal macrophages from septic patients but not on monocytes from healthy donors. Stimulation of human monocytes with LPS and inflammatory cytokines led to a substantial release of sB7-H3. Taken together, our data indicate that significantly elevated plasma sB7-H3 in septic patients may predict a poor outcome. Furthermore, we demonstrate that B7-H3 functions as a costimulator of innate immunity by augmenting proinflammatory cytokine release from bacterial cell wall product-stimulated monocytes/macrophages and may contribute positively to the development of sepsis.
Zhang
Guangbo
G
Clinical Immunology Laboratory, First Affiliated Hospital, Soochow University, Suzhou, People's Republic of China.
Wang
Jian
J
Kelly
Justin
J
Gu
Guohao
G
Hou
Jianquan
J
Zhou
Yinghui
Y
Redmond
H Paul
HP
Wang
Jiang Huai
JH
Zhang
Xueguang
X
D000276:Adjuvants, Immunologic / Q000097:blood / Q000502:physiology* / Q000633:toxicity; D000818:Animals; D015703:Antigens, CD / Q000097:blood / Q000502:physiology*; D060887:B7 Antigens; D018122:B7-1 Antigen / Q000502:physiology; D001425:Bacterial Outer Membrane Proteins / Q000633:toxicity; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000097:blood / Q000502:physiology* / Q000633:toxicity; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009000:Monocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011971:Receptors, Immunologic / Q000097:blood / Q000502:physiology*; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology / Q000401:mortality / Q000473:pathology*; D051195:Toll-Like Receptor 2 / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D060887:B7 Antigens; D018122:B7-1 Antigen; D001425:Bacterial Outer Membrane Proteins; C423237:CD276 protein, human; C486038:Cd276 protein, mouse; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha